International Journal of

Molecular Sciences

Review
The Role of Inflammasome in Abdominal Aortic Aneurysm and
Its Potential Drugs
Suyu Pi 1,2,† , Sizheng Xiong 1,2,† , Yan Yuan 1,2 and Hongping Deng 1,2, *

1 Department of Vascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China;
[email protected] (S.P.); [email protected] (S.X.); [email protected] (Y.Y.)
2 Aortic Abdominal Aneurysm (AAA) Translational Medicine Research Center of Hubei Province,
Wuhan 430060, China
* Correspondence: [email protected]
† These authors contributed equally to this work.

Abstract: Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory
degenerative aortic disease in recent years. At present, there is no other effective intervention except
surgical treatment for AAA. With the aging of the human population, its incidence is increasing
year by year, posing a serious threat to human health. Modern studies suggest that vascular chronic
inflammatory response is the core process in AAA occurrence and development. Inflammasome, a
multiprotein complex located in the cytoplasm, mediates the expression of various inflammatory
cytokines like interleukin (IL)-1β and IL-18, and thus plays a pivotal role in inflammation regulation.
Therefore, inflammasome may exert a crucial influence on the progression of AAA. This article re-
views some mechanism studies to investigate the role of inflammasome in AAA and then summarizes
several potential drugs targeting inflammasome for the treatment of AAA, aiming to provide new
ideas for the clinical prevention and treatment of AAA beyond surgical methods.

Keywords: abdominal aortic aneurysm; inflammasome; NLRP3; AIM2; inflammation; activation and
regulation; potential drugs

Citation: Pi, S.; Xiong, S.; Yuan, Y.;

1. Introduction
Deng, H. The Role of Inflammasome Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflam-
in Abdominal Aortic Aneurysm and matory degenerative aortic disease in recent years, and it is characterized by the progressive
Its Potential Drugs. Int. J. Mol. Sci. pathological dilatation of the abdominal aortic wall [1,2]. AAA can be diagnosed when
2024, 25, 5001. https://doi.org/ the diameter of a permanently dilated or bulging abdominal aorta is greater than 50%
10.3390/ijms25095001 of normal or the diameter of the abdominal aorta is ≥3 cm in general [3]. Most patients
Academic Editor: Andrea Ghiroldi who develop AAA are usually asymptomatic; however, when the aneurysm expands and
ruptures, its mortality is extremely high [4]. According to reports, even if ruptured AAAs
Received: 7 April 2024 are treated in time, the cases fatality rate is still as high as 50–70%, coupled with the cases
Revised: 29 April 2024
without timely surgery, the ruptured AAAs’ total mortality can be as high as 90% [5]. Its
Accepted: 30 April 2024
risk factors include smoking, gender, age, hypertension, chronic obstructive pulmonary dis-
Published: 3 May 2024
ease, hyperlipidemia, and family history of AAA [6–8]. Among all ethnic groups, African
Americans, Asians, and Hispanics are at lower risk than Caucasians [9]. Diabetes mellitus
is a common comorbidity of atherosclerotic disease, although the incidence of AAA in
Copyright: © 2024 by the authors.
diabetic patients is low [10].
Licensee MDPI, Basel, Switzerland. Current guidelines recommend surgical treatment for AAA if the maximum diameter
This article is an open access article is at least 5.5 cm in men (or 5.0 cm in women). Surgery is also recommended for rapidly
distributed under the terms and progressive AAA (≥1 cm/year), symptomatic AAA, ruptured AAA, and AAA with ec-
conditions of the Creative Commons centric or cystic structures [11,12]. Surgery is divided into open surgery and endovascular
Attribution (CC BY) license (https:// repair surgery, but both have corresponding defects and complications. For example, open
creativecommons.org/licenses/by/ surgery for the treatment of abdominal aortic aneurysm is technically mature and has good
4.0/). long-term effects, but its main drawbacks are significant surgical trauma, a large amount

Int. J. Mol. Sci. 2024, 25, 5001. https://doi.org/10.3390/ijms25095001 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2024, 25, 5001 2 of 17

of bleeding, and long postoperative recovery time [13]. Although endovascular repair
surgery is minimally invasive, it can be interfered with by the anatomical conditions of
the aneurysm, which may lead to a severe insufficient anchoring area, resulting in serious
complications such as internal leakage or stent displacement, so the widespread use of
endovascular techniques has also been limited [14,15]. In addition, the management of
small AAA (diameter less than 5 cm) is mainly focused on monitoring, and there is no
clear drug that can alleviate the progression of small AAA. Clinical trial results show that
statins or doxycycline have no obvious inhibitory effect on the growth of AAA [16]. As a
result, it is crucial to clarify the molecular regulatory mechanisms of AAA occurrence and
development in order to identify potential drug targets.
Modern studies have identified aortic extracellular matrix (ECM) degradation, the
apoptosis of vascular smooth muscle cells (VSMCs), and vascular chronic inflammatory
response as the three basic pathological processes in the pathogenesis of AAA [17]. Of
these, vascular chronic inflammatory response is the core process. The cytokines released
by inflammatory cells not only exacerbate ECM degradation but also lead to the apoptosis
of VSMCs [18]. For example, interleukin (IL)-1β, IL-6, IL-33, and other stimuli prompt
macrophages or VSMCs to secrete matrix metalloproteinases (MMPs) that degrade elastin
and collagen, leading to the apoptosis of VSMCs and ECM degradation, thereby disrupting
the stability of the aortic wall architecture [19]. It has been demonstrated in animal experi-
ments that the use of an IL-1β receptor inhibitor (anakinra) can effectively inhibit mouse
AAA formation induced by porcine pancreatic elastase (PPE) perfusion [20]. Therefore,
inflammasome regulating the secretion of cytokines like IL-1β and IL-18 may significantly
influence AAA progression, which has been recognized as a chronic inflammatory disease.

2. Inflammasome
As a significant component of the innate immune system, inflammasome has been
one of the research hotspots in the field of innate immunity since it was first proposed
by Martinon et al. [21] in 2002. Inflammasome, a multiprotein complex located in the
cytoplasm, is mainly expressed in monocytes/macrophages and can also be expressed
in dendritic cells, neutrophils, and certain non-immune cells [22,23]. At present, the
inflammasomes that have been found mainly include NLRP1 inflammasome, NLRP3
inflammasome, NLRC4 inflammasome, IPAF inflammasome, and AIM2 inflammasome.
Inflammasome mainly consists of three components: receptor protein (a member of the
NLR or ALR family), adaptor protein apoptosis-associated speck-like protein containing a
caspase recruitment domain (ASC), and effector protein caspase-1 [24,25].
Therefore, as a multiprotein complex assembled by pattern recognition receptors
(PRRs) in the cytoplasm, inflammasome can recognize and amplify various injury or stimu-
lation signals from pathogen-associated molecular patterns (PAMPs) or damage/danger-
associated molecular patterns (DAMPs), thereby playing a central role in mediating inflam-
mation [26,27]. The activation of inflammasome promotes the self-cleavage of pro-caspase-1
to produce the active effector protein caspase-1, which further cleaves pro-IL-1β, pro-IL-18,
and gasdermin D (GSDMD). Immediately, the N-terminal fragment of GSDMD (GSDMD-
N) forms oligomeric pores in the cell membrane that mediate the osmotic swelling and
death of inflammatory cells (e.g., macrophages), followed by releasing inflammatory fac-
tors like IL-1β and IL-18, which was formerly known as the pyroptosis of inflammatory
necrosis [28]. Apart from this canonical pathway, pyroptosis and inflammasome activa-
tion can also be mediated through the non-canonical caspase-4/5/11 pathway or a newly
discovered caspase-3/gasdermin E (GSDME) pathway [29,30]. Thus, pyroptosis has been
redefined as gasdermin-mediated lytic cell death [31].
Recent research has focused more on NLRP3 inflammasome and AIM2 inflamma-
some, which have been shown to play important roles in various macrophage-driven
inflammation-related diseases. Moreover, studies have continuously pointed out that in-
flammasome activation is a notable link in the pathogenesis of aneurysms. For example,
in human cerebral aneurysm tissue, the expression levels of NLRP3 inflammasome com-
 flammasome activation is a notable link in the pathogenesis of aneurysms. For example
in human cerebral aneurysm tissue, the expression levels of NLRP3 inflammasome com
ponents and their downstream products were as follows: ruptured group > unruptured
group > normal group [32]. Moreover, the genetic deletion of NLRP3 or pharmacologica
Int. J. Mol. Sci. 2024, 25, 5001
inhibition of NLRP3 inflammasome with glyburide reduced the rate of thoracic aortic an
3 of 17

eurysm formation in mice induced by high-fat diet and angiotensin II (Ang II) [33]. Thus
the following sections provide an in-depth analysis of the mechanisms of these two in
ponents and their downstream products were as follows: ruptured group > unruptured
flammasomes
group in AAA
> normal group and
[32]. discusses
Moreover, thepotential targeted
genetic deletion of drugs.
NLRP3 or pharmacological
inhibition of NLRP3 inflammasome with glyburide reduced the rate of thoracic aortic
3. NLRP3formation
aneurysm Inflammasome
in micein AAA by high-fat diet and angiotensin II (Ang II) [33].
induced
Thus, Nucleotide-binding
the following sections oligomerization domain-like
provide an in-depth receptor
analysis of the familyofpyrin
mechanisms thesedomain-con
two
inflammasomes in AAA and discusses potential targeted drugs.
taining 3 (NLRP3) inflammasome is one of the well-characterized inflammasomes discov
3.ered in recent
NLRP3 years, with
Inflammasome a relative molecular mass of approximately 700 kDa. NLRP
in AAA
inflammasome is composed
Nucleotide-binding of its central
oligomerization protein
domain-like NLRP3,
receptor familyadaptor protein ASC, and effec
pyrin domain-containing
tor protein caspase-1. The central protein NLRP3 also includes
3 (NLRP3) inflammasome is one of the well-characterized inflammasomes discovered the following three parts
in recent
the C-terminal
years, leucine-rich
with a relative molecularrepeat
mass ofdomain (LRR), 700
approximately which
kDa.isNLRP3
responsible for ligand
inflammasome is recogni
tion; the ofnucleotide-binding
composed its central protein NLRP3, oligomerization
adaptor proteindomain ASC, and(NOD/NACHT) in the middle
effector protein caspase-1.
which
The is the
central coreNLRP3
protein structure of inflammasome
also includes the followingand threeexhibits
parts: theATPase activity
C-terminal and mediate
leucine-rich
oligomerization
repeat domain (LRR), of NLRP3
which ismolecules;
responsible and the N-terminal
for ligand recognition;pyrin domain (PYD), involved
the nucleotide-binding
in signal transduction
oligomerization [34]. As an intracellular
domain (NOD/NACHT) in the middle, adaptor
which protein,
is the coreASC consists
structure of two parts
of inflam-
masome and exhibits ATPase activity and mediates oligomerization of NLRP3 molecules; and
the N-terminal PYD and the C-terminal caspase recruitment domain (CARD). When th
the N-terminal pyrin domain (PYD), involved in signal transduction [34]. As an intracellular
central protein NLRP3 is stimulated by activation signals, ASC interacts with the PYD o
adaptor protein, ASC consists of two parts, the N-terminal PYD and the C-terminal caspase
NLRP3 viadomain
recruitment homotypic PYD,
(CARD). Whenfollowed by recruiting
the central pro-caspase-1
protein NLRP3 is stimulated with
by CARD–CARD
activation in
teractions,
signals, ASC resulting in inflammasome
interacts with the PYD of NLRP3 oligomerization
via homotypic (Figure 1) [35].byThen,
PYD, followed pro-caspase
recruiting
1 cleaves itself into active caspase-1, which subsequently
pro-caspase-1 with CARD–CARD interactions, resulting in inflammasome oligomerizationmediates pro-IL-1β, pro-IL-18
and GSDMD
(Figure to cleave
1) [35]. Then, into active
pro-caspase-1 subunits,
cleaves itself intotriggering pyroptosis
active caspase-1, and inflammation
which subsequently me- [36]
Due to
diates its ability
pro-IL-1β, to be activated
pro-IL-18, and GSDMD by manifold types
to cleave into of pathogens
active or danger
subunits, triggering signals, NLRP
pyroptosis
inflammasome
and inflammation [36].can Due
playtoaitspivotal
ability torole in various
be activated diseasetypes
by manifold processes, namely,
of pathogens cryopyrin
or dan-
ger signals, NLRP3 inflammasome can play a pivotal role in various disease processes, namely,
associated periodic syndromes (CAPS) [37,38], Alzheimer’s disease [39], rheumatoid ar
cryopyrin-associated periodic syndromes (CAPS) [37,38], Alzheimer’s disease [39], rheumatoid
thritis [40], and others [41]. Additionally, many studies have suggested a correlation be
arthritis [40], and others [41]. Additionally, many studies have suggested a correlation between
tween inflammasome
NLRP3 NLRP3 inflammasome and AAA inand AAA
recent in recent years.
years.

Figure 1. The structure of NLRP3 inflammasome. Nucleotide-binding oligomerization domain-like

Figure 1.
receptor The structure
family of NLRP3 inflammasome.
pyrin domain-containing Nucleotide-binding
3 (NLRP3) inflammasome oligomerization
is a multiprotein complex domain-lik
as-
sembled using three components: the adaptor apoptosis-associated speck-like protein containingcomplex
receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein a as
sembled using three components: the adaptor apoptosis-associated speck-like protein
caspase-recruitment domain (ASC), NLRP3, and pro-caspase-1. When the central protein NLRP3 is containing
caspase-recruitment domain (ASC), NLRP3, and pro-caspase-1. When the central protein NLRP3 i
stimulated by activation signals, ASC interacts with the N-terminal pyrin domain (PYD) of NLRP3
stimulated by activation signals, ASC interacts with the N-terminal pyrin domain (PYD) of NLRP
via homotypic PYD, followed by recruiting pro-caspase-1 via the C-terminal caspase recruitment do-
via homotypic PYD, followed by recruiting pro-caspase-1 via the C-terminal caspase recruitmen
main (CARD)–CARD interactions, resulting in the oligomerization of inflammasome. Pro-caspase-1
subsequently cleaves itself into caspase-1 and then releases catalytically active subunits p20/10. LRR,
leucine-rich repeat; NACHT, nucleotide-binding oligomerization domain.
Int. J. Mol. Sci. 2024, 25, 5001 4 of 17

For example, in 2011, Roberts et al. [42] used a comparative detection of arterial wall
samples from 1151 AAA patients and 727 non-AAA patients to establish that NLRP3
homozygous gene rs35829419 and its downstream product IL-1β were significantly over-
expressed in the AAA group, suggesting that NLRP3 inflammasome did have a direct or
indirect regulatory effect on AAA occurrence. In a subsequent study, NLRP3 and caspase-1
were found to be up-regulated in macrophages from human and mouse AAA tissues,
while knockout of NLRP3 and caspase-1 revealed that the incidence and severity of AAA
in mice induced by Ang II, the infiltration of inflammatory cells, and the expression of
mitochondrial reactive oxygen species (mtROS) in adventitial macrophages were all in-
hibited [43]. The above outcomes suggested that Ang II might promote the assembly of
NLRP3 inflammasome in macrophages and IL-1β release through angiotensin II type 1
(AT1) receptor or the mtROS-dependent pathway, leading to the generation of inflammation
in the early stage of AAA [43]. Wu et al. [44] also reported an interesting finding in 2017,
which demonstrated that caspase-1 could directly cleave and degrade contractile proteins
of VSMCs at the arterial wall, showing that NLRP3 inflammasome might play a novel role
in AAA. In addition, Ren et al. [45] observed that NLRP3 inflammasome in macrophages
directly activated MMP-9 by cutting its own N-terminal inhibitory domain, while using a
strong selective NLRP3 inflammasome inhibitor MCC950 to block inflammasome activation
in macrophages could prevent the formation of an aortic aneurysm. Likewise, hyperho-
mocysteinemia (HHcy) exacerbated two different murine models of AAA by inducing the
NLRP3 inflammasome activation in macrophages to stimulate inflammation, whereas the
administration of folic acid reversed the HHcy-aggravated AAA with attenuated outer
membrane inflammasome activation [46]. In short, the silence of NLRP3 inflammasome
significantly diminishes AAA formation.
The results of Sun et al.’s [28] recent study indicated that the P2X7 receptor was highly
expressed in calcium chloride (CaCl2 ) and Ang II-induced mouse AAA models, as well as in
human AAA specimens, and co-localized with the macrophage marker CD68. Mechanically,
the macrophage-derived purinergic receptor P2X7 is a ligand-gated cation channel. When
activated by extracellular ATP, the P2X7 receptor promotes the influx of Na+ and Ca2+ ,
as well as the efflux of K+ , subsequently mediates downstream NLRP3 inflammasome
activation, and then initiates canonical pyroptosis. The ensuing vascular inflammatory
response propels an increase in MMPs and ROS, thus facilitating the formation of AAA.
Furthermore, either the knockout of the P2X7 receptor or the use of the P2X7 receptor
antagonist A438079 notably reduced the formation of AAA in experimental mouse models,
whereas the agonist ATP-γ-S remarkably accelerated AAA progression [28]. Previously,
another study reported that Pannexin-1 (Panx1) on vascular endothelial cells, a channel
that releases ATP, stimulated macrophage activation by activating P2X7 receptor and
mitochondrial DNA (mtDNA) release to increase the secretion of IL-1β as well as high-
mobility group protein B1 (HMGB1, a notable late-stage inflammatory mediator), followed
by promoting the formation of AAA [47].

4. AIM2 Inflammasome in AAA

Absent in melanoma 2 (AIM2) is a 344-amino acid protein with a relative molecu-
lar mass of about 39 kDa, encoded by the AIM2 gene (1485 kb) on human chromosome
1q22, which belongs to the interferon-inducible gene family [48]. AIM2 is the only known
member of the natural immunoreceptor family that recognizes the presence of cytoplasmic
double-stranded DNA (dsDNA) to assemble AIM2 inflammasome, which is a macromolec-
ular complex including AIM2, adaptor protein ASC, and caspase-1 [49,50]. AIM2 can be
expressed in vascular cells like macrophages, arterial endothelial cells, and VSMCs [51],
localized in the cytoplasm, mitochondria, and nucleus [52]. It has two important domains,
namely, the N-terminal PYD and the C-terminal hematopoietic interferon-inducible nuclear
antigens with 200 amino acid repeats (HIN-200) domain. The latter has the advantage of
dsDNA recognition [53], as it contains two oligonucleotide/oligosaccharide-binding (OB)
folded subdomains with high affinity for DNA, which are 70 to 150 amino acids in length
 binding of the HIN-200 domain to the sugar phosphate b
the self-inhibition of AIM2 [55]. Thus, in the AIM2 inflamm
Int. J. Mol. Sci. 2024, 25, 5001 tor protein that specifically recognizes and binds5 ofcytosol 17

domain, while ASC connects upstream AIM2 with downs

components, thereby priming a canonical activation pathw
and used for binding to single-stranded DNA [54]. During the steady state, the PYD and
HIN-200 domain interact to maintain AIM2 molecular self-inhibition, while the binding
inflammasome,
of the HIN-200 domain to which triggers
the sugar phosphate pyroptosis
backbone of dsDNA can and inflammato
relieve the self-
inhibition of AIM2 [55]. Thus, in the AIM2 inflammasome, AIM2 acts as an initiator protein
markably, it hasand
that specifically recognizes also
bindsbeen
cytosolicfound thatitsAIM2
dsDNA through HIN-200 inflammasom
domain, while

cal NLRP3
priming a inflammasome activation via the pores formed
ASC connects upstream AIM2 with downstream pro-caspase-1-activating components,
thereby canonical activation pathway similar to that of the NLRP3 inflamma-
efflux [57]. Over recent years, many studies have demon
some, which triggers pyroptosis and inflammatory response (Figure 2) [56]. Remarkably,
it has also been found that AIM2 inflammasome could induce the non-canonical NLRP3
inflammasome
inflammasome activation via activation with
the pores formed AAA
by GSDMD anddevelopment as well
subsequent K+ efflux [57].
Over recent years, many studies have demonstrated the correlation of AIM2 inflammasome
activation with AAA development as well.

Figure 2. The structure of AIM2 inflammasome. Absent in melanoma 2 (AIM2) inflammasome is

Figure 2. The structure of AIM2 inflammasome. Absent in mela
a macromolecular complex composed of AIM2, apoptosis-associated speck-like protein containing a
caspase-recruitment domain (ASC), and caspase-1. AIM2 has two important domains, namely, the
macromolecular complex composed of AIM2, apoptosis-associa
N-terminal pyrin domain (PYD) and the C-terminal hematopoietic interferon-inducible nuclear antigens
caspase-recruitment domain (ASC), and caspase-1. AIM2 has tw
with 200 amino acid repeats (HIN-200) domain. The latter contains two oligonucleotide/oligosaccharide-
binding (OB) folded subdomains with high affinity for DNA. The PYD and HIN-200 domain interact
N-terminal pyrin domain (PYD) and the C-terminal hematopoie
to maintain AIM2 molecular self-inhibition during the steady state. When the HIN-200 domain is

tigens with 200 amino acid repeats (HIN-200) domain. The latte
stimulated by the presence of cytoplasmic double-stranded DNA (dsDNA), self-inhibition of AIM2 is
removed, ASC acts as an adaptor protein that connects upstream AIM2 with downstream pro-caspase-1
gosaccharide-binding (OB) folded subdomains with high affinit
via the N-terminal PYD-PYD interactions and the C-terminal recruitment domain (CARD)–CARD

domain interact to maintain AIM2 molecular self-inhibition duri

interactions, leading to the assembly of AIM2 inflammasome; subsequently, pro-caspase-1 self-cleaves
and its active subunits p20/10 are released.
200 domain is stimulated by the presence of cytoplasmic double-
bition of AIM2 is removed, ASC acts as an adaptor protein that co
stream pro-caspase-1 via the N-terminal PYD-PYD interactions a
Int. J. Mol. Sci. 2024, 25, 5001 6 of 17

In 2014, Dihlmann et al. [58] initially found that compared with a normal aorta,
AAA specimens with higher inflammatory grade had higher expression levels of AIM2
inflammasome components. Moreover, compared to patients with lower risk of aneurysm
rupture, the expression of AIM2 inflammasome core components (e.g., ASC, caspase-1,
caspase-5) and its downstream product IL-1β were all conspicuously up-regulated in the
peripheral blood single infiltrating lymphocytes of patients at higher risk, suggesting a
correlation between AIM2 inflammasome and AAA rupture as well as indicating that
AAA-associated lymphocytes could carry out AIM2 inflammasome signaling [58]. Another
study [59] reported that the expression of AIM2 in peripheral blood leukocytes such as
granulocytes, monocytes, B lymphocytes, and T lymphocytes was significantly increased
in AAA patients, while the expression levels of other inflammasomes apparently did not
differ between the two groups. After rendering exogenous DNA stimulation in vitro, IL-1β
released by peripheral blood mononuclear cells (PBMCs) was remarkably higher than
that of the control group, revealing that AIM2 inflammasome has a specific role in AAA
development [59]. As indicated by a previous study [60], the expression levels of AIM2
inflammasome and downstream products in the PBMCs of AAA patients were obviously
higher than those of non-AAA patients. However, all of these were reflected in male AAA
patients, and there was no distinct difference between female patients and the control group.
As a consequence, it was pointed out that male PBMCs display a systemic pro-inflammatory
state, whereas primed inflammasomes might be partly responsible for the pathogenesis
of AAA [60].

5. Inflammation Is a Common Feature in AAA and Atherosclerosis

AAA and atherosclerosis are two different but closely related diseases, and abdominal
aortic atherosclerosis is common in middle-aged patients with AAA [61,62]. They share
many similar features, such as inflammatory cell infiltration, matrix degradation, and arte-
rial wall thrombosis, among which aseptic inflammation is a prominent common feature of
these two diseases [63]. Therefore, the analysis of inflammation in atherosclerosis may help
to deepen our understanding of the pathogenesis of AAA. Numerous previous studies
have shown that inflammation in AAA and atherosclerosis is mainly mediated by the
NLRP3 inflammasome [43,64]. In addition to classic cholesterol crystals in atherosclerotic
plaques, which are one of the most potent DAMPs to activate NLRP3 inflammasome in
macrophages [64,65], calcium phosphate crystals and crystals formed by saturated fatty
acids also induce NLRP3 inflammasome activation [66,67]. Some reports have suggested
that P2X7 receptor or hypoxia-mediated K+ efflux and mtROS/mtDNA production con-
tribute to NLRP3 activation, and the subsequent release of active IL-1β induces vascular
inflammation and ultimately leads to atherosclerosis [68–70]. Although both are chronic
inflammatory diseases, AAA is not significantly associated with low-density lipoprotein,
and there is no serious ECM degradation in atherosclerosis, hinting that the mechanisms of
NLRP3 inflammasome activation are different between the two. Therefore, it is necessary to
conduct the in-depth analysis and exploration of the activation and regulatory mechanisms
of the inflammasome in such diseases, which is also the direction of subsequent research.

6. Activation and Regulation Mechanisms of the Inflammasome

It is worth noting that recent studies have shown that the activation of inflammasome
in macrophages needs two consecutive signals: the priming signal (Signal 1) and the activa-
tion signal (Signal 2) [71]. First, PAMPs/DAMPs act as priming signals to bind to Toll-like
receptors (TLRs) and then activate the nuclear factor kappa-light-chain-enhancer of acti-
vated B cells (NF-κB) signaling pathway, thereby increasing the expression of downstream
proteins (e.g., NLRP3, pro-IL-1β, and pro-IL-18) [72]. Then, K+ efflux and the presence
of cytoplasmic dsDNA are activation signals that induce the assembly of NLRP3 inflam-
masome and AIM2 inflammasome, respectively. Furthermore, NLRP3 inflammasome
activation is usually carried out with the help of lysosome-released cathepsins, mtROS,
and mitochondrial DNA (mtDNA) (Figure 3) [73]. As Shridas et al. [74] found, the lack of
 Int. J. Mol. Sci. 2024, 25, 5001 7 of 17

, x FOR PEER REVIEW serum amyloid A (SAA) could prevent the formation of AAA in mice induced by Ang 7 of
II, 17
whereas its increase contributed to NLRP3 inflammasome activation in macrophages and
the increase in IL-1β secretion. Mechanistically, SAA may activate NLRP3 inflammasome
in the form of ROS production, cathepsin B activation, and K+ efflux. Interestingly, high-
formation and inflammasome activation, which might be because, as a lipophilic apolipo-
density lipoprotein (HDL) eliminated the ability of SAA to stimulate ROS formation and
inflammasome activation, which might be because, as a lipophilic apolipoprotein, many
protein, many properties
properties of SAAareare
of SAA lostlost
whenwhen combined
combined with HDLwith
[75]. HDL [75].

Figure 3. Two consecutive signals are requisite for inflammasome activation. The activation of inflamma-
Figure 3. Two consecutive signals are requisite for inflammasome activation. The activation of in-
some requires the priming signal (Signal 1) and the activation signal (Signal 2). Priming signal (Signal 1):
flammasome requires the priming signal
pathogen-associated (Signal
molecular patterns1)(PAMPs)
and theoractivation signal (Signal
damage/danger-associated 2). Priming
molecular patternssig-
nal (Signal 1): pathogen-associated molecular patterns (PAMPs) or damage/danger-associated
(DAMPs) such as lipopolysaccharides (LPS) act as priming signals to activate the nuclear factor kappa- mo-
lecular patterns (DAMPs) such as lipopolysaccharides
light-chain-enhancer (LPS) act
of activated B cells (NF-κB) signaling as priming
pathway signals
through binding to activate
to Toll-like receptors the
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway through
(TLRs), thereby increasing the expression of downstream proteins such as nucleotide-binding oligomer-
binding to Toll-likeization
receptors (TLRs), thereby increasing the expression of downstream proteins
domain-like receptor family pyrin domain-containing 3 (NLRP3), pro-interleukin (IL)-1β, and
pro-IL-18. Activation signal (Signal 2): under the stimulation of PAMPs/DAMPs, K+ efflux and the
such as nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing
presence of cytoplasmic double-stranded DNA (dsDNA) are common activation signals that induce the
3 (NLRP3), pro-interleukin
assembly of(IL)-1β, and pro-IL-18.
NLRP3 inflammasome Activation
and absent signal
in melanoma (Signal
2 (AIM2) 2): under respectively,
inflammasome, the stimulation
and
of PAMPs/DAMPs, other K efflux
+ and
upstream theincluding
events presence of cytoplasmic
lysosome-released double-stranded
cathepsins, DNAoxygen
mitochondrial reactive (dsDNA)species are
common activation (mtROS),
signalsandthat induce the
mitochondrial DNAassembly
(mtDNA) are ofalso
NLRP3
neededinflammasome
for NLRP3 inflammasomeand absent
activation.in mela-
Then,
noma 2 (AIM2) inflammasome, respectively,
inactive pro-caspase-1 transforms intoand other
active upstream
caspase-1 eventswhich
via self-cleavage, including
subsequentlylysosome-re-
mediates
leased cathepsins, pro-IL-1β
mitochondrial reactive oxygen species (mtROS), and mitochondrial DNA
and pro-IL-18 to cleave into mature IL-1β and IL-18, triggering inflammation. Gasdermin D
(GSDMD) is also cleaved by caspase-1 into the N-terminal fragment of GSDMD (GSDMD-N), which
(mtDNA) are also needed for NLRP3 inflammasome activation. Then, inactive pro-caspase-1 trans-
forms oligomeric pores in the cell membrane and releases inflammatory factors such as IL-1β and IL-18,
forms into active caspase-1
leading to via self-cleavage, which subsequently mediates pro-IL-1β and pro-IL-18
pyroptosis.
to cleave into mature IL-1β and IL-18, triggering inflammation. Gasdermin D (GSDMD) is also
cleaved by caspase-1 into the N-terminal fragment of GSDMD (GSDMD-N), which forms oligomeric
pores in the cell membrane and releases inflammatory factors such as IL-1β and IL-18, leading to
pyroptosis.
Int. J. Mol. Sci. 2024, 25, 5001 8 of 17

Post-translational modifications (PTMs), like phosphorylation and de-ubiquitination,

have been revealed to induce the rapid priming of NLRP3 protein [63]. Similarly, other
ion flux events (e.g., Ca2+ mobilization, Na+ influx, and Cl− efflux) are also thought to
promote the activation of NLRP3 inflammasome, but their definite regulatory mechanisms
are not comprehended completely and still contentious [76]. Some recent studies have
found that upon inflammasome being activated by Signal 2, NIMA-related kinase 7 (NEK7)
can regulate NLRP3 inflammasome oligomerization and activation via binding to NLRP3
protein, which is considered to be the target of itaconate and its derivative 4-octyl itaconate
(4-OI) [77]. A study in 2018 showed that multiple NLRP3 activators caused the disassembly
of the trans-Golgi network into a dispersed trans-Golgi network, which could be a platform
to contribute to the assembly and activation of NLRP3 inflammasome [78]. Additionally, the
expression and activity of NLRP3 inflammasome can be regulated by diverse mechanisms,
for instance, PTMs, microRNAs, and endogenous modulators like CARD-only proteins
and pyrin-only proteins [79–81]. From this perspective, regulatory mechanisms underlying
inflammasome activation may be more intricate than prior appreciation, and they seem
likely to vary according to the type of cell and stimulus [82]. Therefore, future research
should further elucidate the molecular mechanisms involved in inflammasome.
Interestingly, inflammasome-mediated pyroptosis and inflammation appear to exhibit
distinct manifestations at different stages of AAA progression. As a study indicated
in 2019, the expression frequencies of NLRP3, AIM2, and caspase-5 in macrophages and
lymphocytes were significantly lower in samples from the control group than from the AAA
group. However, as AAA lesions progressed, the expression and activity of inflammasomes
gradually decreased [83]. Part of the explanation may be that itaconate confers tolerance
to late inflammasome activation. As shown by Bambouskova et al. [84], the accumulation
of endogenous itaconate in response to prolonged lipopolysaccharide (LPS) stimulation
blocked caspase-1 activation and GSDMD processing, but it was also found that the Cys77
of GSDMD might be the target of itaconate modification produced by mouse bone marrow-
derived macrophages (BMDMs). Another study reported that necrotic cell debris from
autologous cells promoted the expression of AIM2 and NLRP3 inflammasomes in the
VSMCs of advanced AAA tissue, followed by activating downstream inflammatory flare,
suggesting that inflammasome might serve as a “bridge” between VSMC dysfunction and
inflammatory response [85].

7. Potential Drugs Targeting Inflammasome for the Treatment of AAA

The above mechanism studies demonstrate that inflammasome is so involved in the
occurrence and development of AAA that it could become a potential target for drug
treatment of AAA. Based on the complicated regulatory mechanisms of inflammasome
activation, the upstream signaling, assembly of inflammasome, downstream caspase-1
activation, GSDMD cleavage, and inflammatory cytokines produced by inflammasome
may all become the targets for the direct or indirect inhibition of inflammasome. In practice,
the CANTOS trial using canakinumab revealed that IL-1-targeted therapy was effective in
preventing atherothrombotic events [86]. Nevertheless, canakinumab is not only costly, but
the long-term inhibition of IL-1 signaling also has the potential to cause adverse events,
for instance, infection and immune homeostasis disorder [82]. Additionally, ASC and
caspase-1 are involved not only in NLRP3 inflammasome but also in other inflammasomes
that contribute to pathogen clearance (e.g., NLRP1 and AIM2 inflammasomes). Hence,
pharmacological inhibitors that more specifically target the inflammasome could be a better
choice to treat inflammasome-related diseases. Recently, several studies have reported
the effectiveness of pharmacological inhibitors targeting NLRP3 inflammasome or AIM2
inflammasome in the treatment of experimental AAAs (Table 1).
Int. J. Mol. Sci. 2024, 25, 5001 9 of 17

Table 1. Influence of pharmacological inhibitors targeting NLRP3 inflammasome or AIM2 inflamma-

some on experimental AAAs.

Animal Species
Drug Name AAA Model Potential Mechanism Experimental Effect Cite
and Strain

• Blocked the expression and

• Block the ATPase domain activity of MMP-9
of NLRP3 in macrophages
Wild-type Ang II infusion • Suppress both canonical • Reduced the degradation of [45]
MCC950 and non-canonical
C57BL/6 mice and high-fat diet VSMCs’ contractile proteins [87]
pathways of NLRP3 and ECM damage
inflammasome activation • Inhibited the formation
of AAA

• Inhibited the degradation of

• Inhibit ATP-sensitive VSMCs’ contractile proteins
K+ channels mediated by NLRP3
Wild-type Ang II infusion [44]
Glyburide • Suppress ASC aggregation inflammasome-caspase-1
C57BL/6 mice and high-fat diet [88]
downstream of P2X7 receptor • Reduced aneurysmal aortic
diameter and
aneurysm incidence

• Bind to NLRP3 • Attenuated aortic infiltration

NACHT domain of mast cells and T cells
Wild-type • Abolish the direct [89]
• Decreased MMP-9 activity
Tranilast Sprague Dawley CaCl2 induction NLRP3-NLRP3 interaction [90]
• Reduced aneurysmal aortic
rats • Impair the endogenous [91]
dilation and preserved
NLRP3-ASC interaction medial elastin

• Block kinase activity of IKKβ • Silenced AEBP1 in VSMCs

to inhibit NF-κB pathway • Reduced the expression of
Wild-type
• Alkylate cysteine residues in inflammatory factors [92]
Bay 11-7082 Sprague Dawley PPE perfusion
the ATPase domain of NLRP3 and MMPs [93]
rats
• Inhibit NLRP3 ATPase activity • Inhibited the progression
of AAA

• Regulate PSAP ubiquitination

type by binding to • Down-regulated
PSAP 577-919 NF-κB-mediated cytokine
• Inhibit the activation production and α4
Wild-type of the NF-κB pathway integrin expression [94]
Andrographolide PPE perfusion and block NLRP3
C57BL/6 mice • Attenuated the infiltration of [95]
inflammasome assembly inflammatory cells in the aorta
• Prevent AIM2 translocation • Suppressed the progression
into the nucleus to sense of AAA
damaged dsDNA

• Inhibited inflammatory cell

• Inhibit the activation of NF-κB infiltration and
pathway and scavenge ROS cytokine release
• Block the oligomerization of • Reduced the expression of
Wild-type ASC to inhibit the assembly [96]
Quercetin CaCl2 induction MMPs and cathepsins while
C57BL/6 mice and activation of NLRP3 [97]
promoting TIMP-1
inflammasome and AIM2 gene expression
inflammasome • Hindered the expansion and
progression of AAA

AAA, abdominal aortic aneurysm; AEBP1, adipocyte enhancer-binding protein 1; AIM2, absent in melanoma 2;
Ang II, angiotensin II; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain;
CaCl2 , calcium chloride; dsDNA, double-stranded DNA; ECM, extracellular matrix; IKKβ, inhibitor of nuclear
factor kappa B kinase subunit beta; MMPs, matrix metalloproteinases; NACHT, nucleotide-binding oligomeriza-
tion domain; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, nucleotide-binding
oligomerization domain-like receptor family pyrin domain-containing 3; PPE, porcine pancreatic elastase; PSAP,
puromycin-sensitive aminopeptidase; ROS, reactive oxygen species; TIMP, tissue inhibitor of metalloproteinase;
VSMCs, vascular smooth muscle cells.
Int. J. Mol. Sci. 2024, 25, 5001 10 of 17

7.1. MCC950
MCC950 is currently the most well-studied potent, selective small-molecule NLRP3
inhibitor (also called CP-456,773 or CRID3) [35]. Surprisingly, MCC950 exhibits high
selectivity towards NLRP3, which does not impede any of pathways driven by other in-
flammasomes. Moreover, it suppresses all known stimuli that can cause NLRP3 activation
to date [98]. A previous study found that MCC950 could block pro-IL-1β processing medi-
ated by caspase-1 [99]. Subsequently, Coll et al. [100] also demonstrated that MCC950 was
capable of blocking both canonical and non-canonical pathways of NLRP3 inflammasome
activation as well as IL-1β production by eliminating ASC oligomerization in mouse and
human macrophages. Strikingly, a recent study pointed out that its mechanism is due to
the direct binding of MCC950 to the Walker B motif on the NACHT domain of NLRP3,
followed by blocking ATP hydrolysis and NLRP3 inflammasome formation [87]. Based on
these, as Ren et al. [45] described, the use of MCC950 blocked the expression and activity
of MMP-9 in macrophages, reduced the degradation of VSMCs’ contractile proteins and
ECM damage, and ultimately inhibited the formation of aortic aneurysm in Ang II-infused
hypercholesterolemic mice. Regrettably, the clinical development of MCC950 has been
halted because of its hepatotoxicity [98].

7.2. Glyburide
Glyburide is a sulfonylurea-based compound used to treat type 2 diabetes (T2D).
Its mechanism of action involves the inhibition of ATP-sensitive K+ (K+ ATP ) channels in
pancreatic β cells to stimulate insulin secretion [101]. A previous study revealed that
glyburide could prevent PAMPs, DAMPs, and the crystal-induced activation of NLRP3
inflammasome in BMDMs, while it did not alter NLRP3 expression or suppress AIM2 or
NLRC4, suggesting that glyburide suppressed NLRP3 upstream of ASC [88]. Moreover,
glyburide also effectively blocked caspase-1 activation and IL-1β secretion when tested
against stimuli that are not dependent on the P2X7 receptor but require TLR4 signaling,
indicating that it functions downstream of the P2X7 receptor [88]. In addition, as mentioned
above, in 2017, Wu et al. [44] also observed that glyburide inhibited the degradation
of VSMCs’ contractile proteins mediated by NLRP3 inflammasome-caspase-1, reducing
aneurysmal aortic diameter and aneurysm incidence. Nonetheless, glyburide exerts its
inhibitory effect at a considerably high in vivo dose, which can induce the occurrence of
hypoglycemia, so its use remains limited to T2D [98].

7.3. Tranilast
Tranilast, a tryptophan metabolite analogue, is also a specific inhibitor of NLRP3
inflammasome but has no effect on NLRC4 or AIM2 inflammasomes. Indeed, it has
been revealed that tranilast blocked NLRP3 oligomerization via binding to the NLRP3
NACHT domain and abolishing the direct NLRP3–NLRP3 interaction so that it reduced
caspase-1 activation and IL-1β secretion [89]. Moreover, tranilast impairs the endogenous
NLRP3–ASC interaction but not the NLRP3-NEK7 interaction, thus increasing its likeli-
hood of directly targeting NLRP3. Furthermore, it does not hinder the upstream signaling
events of NLRP3 inflammasome, such as NLRP3 and pro-IL-1β expression, K+ efflux,
chloride efflux, ROS production, and mitochondrial damage [90]. As early as 2008, a study
found that the administration of tranilast could suppress the CaCl2 -induced dilation of the
AAA arterial wall, which is associated with the retention of medial elastin, the attenuation
of mural mast cells and lymphocyte infiltration, reduction in neovascularization, and de-
creased MMP-9 activity [91]. Tranilast is a reasonably safe compound that patients have
shown good tolerance of when tested at high dose levels [102]. Given its high safety profile
in clinic, it may have important implications for treating NLRP3-driven diseases.

7.4. Bay 11-7082

Bay 11-7082 is a phenyl vinyl sulfone that inhibits the NF-κB pathway by blocking the
kinase activity of inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) [103]. As
Int. J. Mol. Sci. 2024, 25, 5001 11 of 17

Ren et al. [92] reported, in a rat AAA model perfused with PPE, the addition of Bay 11-7082
silenced adipocyte enhancer-binding protein 1 (AEBP1) in VSMCs, resulting in NF-κB path-
way inhibition and the reduced expression of inflammatory factors and MMPs, followed by
the inhibition of the progression of AAA. Although this effect could theoretically suppress
the priming stage of NLRP3 via inhibiting the activation of NF-κB, there is evidence that
the inhibition of LPS-induced NLRP3 inflammasome activation in macrophages might not
be related to this [93]. The mechanism may be explained by the fact that, as a Michael
receptor, Bay 11-7082 alkylates cysteine residues in the ATPase domain of NLRP3, blocking
NLRP3 ATPase activity, thus inhibiting NLRP3-induced ASC oligomerization. Moreover,
when the vinyl sulfone moiety of Bay 11-7082 was removed, it changed from active to
inactive. Therefore, compared with other inflammasomes, Bay 11-7082 also showed the
selective inhibition of NLRP3 inflammasome [93]. Vinyl sulfone derivatives have been used
as antiparasitic agents in dogs and mice over recent years [104], and these preclinical trials
have suggested that this class of compounds is well tolerated, non-mutagenic, and has an
appropriate pharmacokinetic profile as well as readily penetrating cell membranes [93].
Bay 11-7082 and other vinyl sulfone derivatives represent good candidates for the drug
treatment of inflammasome-related diseases.

7.5. Andrographolide
Andrographolide is an active component extracted from Andrographis paniculate, which
has multifarious pharmacological effects [105]. Previously, one study showed that andro-
grapholide inhibited the activation of the NF-κB pathway in macrophages and VSMCs,
thereby attenuating the infiltration of inflammatory cells in the aorta by down-regulating
NF-κB-mediated cytokine production and α4 integrin expression, which ultimately sup-
pressed the progression of the PPE-perfused AAA model in mice [94]. Andrographolide
also regulated the ubiquitination type of target protein puromycin-sensitive aminopepti-
dase (PSAP) by binding to PSAP 577-919, which shifted PSAP from K63 ubiquitination
modification that promoted TLR4-NF-κB signaling to K48 ubiquitination modification and
oligomerization. In turn, PSAP interacted with the NOD-LRR domain of NLRP3 through
1-577 to block inflammasome assembly and thus inhibit caspase-1 activation, realizing a
short-circuit regulation of the inflammatory response. In addition, the therapeutic effect
of andrographolide may also be associated with the inhibition of AIM2 inflammasome.
As reported by Gao et al. [95], andrographolide significantly impeded the activation of
AIM2 inflammasome and pyroptosis in macrophages via preventing AIM2 translocation
into the nucleus to sense radiation-induced dsDNA damage, thereby mitigating radiation-
induced lung inflammation and fibrosis. Andrographolide has been used clinically for
many years, with low toxicity and known pharmacokinetic parameters [105]. In conclusion,
andrographolide provides a potential pharmacological opportunity for us to delay disease
progression in AAA patients.

7.6. Quercetin
Quercetin is a flavonoid with anti-inflammatory activity [106]. In 2012, it was found
that in the CaCl2 -induced mouse AAA model, macrophage and CD3+ T cell infiltration in
aortic tissues, the activation of NF-κB pathway, and inflammatory cytokine release were
all inhibited after quercetin treatment [96]. Notably, quercetin reduced the expression
of MMP-2, MMP-9, cathepsin B, and cathepsin K while promoting the tissue inhibitor
of metalloproteinase (TIMP)-1 gene expression, subsequently hindering the expansion
and progression of AAA [96]. Over recent years, several studies have indicated that
quercetin could indirectly inhibit the expression and activation of NLRP3 inflammasome
via inhibiting NF-κB pathway activation and scavenging ROS, thus playing a protective
role in various inflammatory diseases [106–108]. In 2017, Domiciano et al. [97] further
revealed that quercetin could also directly block the oligomerization of the inflammasome
component ASC in macrophages, followed by inhibiting the assembly and activation of
NLRP3 inflammasome and AIM2 inflammasome, which was evidenced by its inhibition
Int. J. Mol. Sci. 2024, 25, 5001 12 of 17

of constitutive activated NLRP3 inflammasome. As a consequence, it reduced IL-1β

secretion mediated by NLRP3 inflammasome and AIM2 inflammasome but not NLRC4
inflammasome in a dose-dependent manner, suggesting that the inhibition of activation
signals by quercetin was limited to ASC-dependent inflammasomes [97]. In summary,
these studies indicate that quercetin may block inflammasome activation in a variety of
ways, which holds great promise for treating multiple inflammatory diseases such as AAA.

8. Conclusions
Inflammasome is the central node of immune sensing within the innate immune
system, and aberrant inflammasome activation is the core aspect of deleterious chronic
inflammation. Accumulating evidence suggests that inflammasomes such as NLRP3 in-
flammasome and AIM2 inflammasome contribute to the pathogenesis of AAA, a chronic
inflammatory disease, and are considered promising targets to prevent or treat this disease.
Therefore, the studies that profoundly explore the role of inflammasome in AAA can en-
hance our understanding of the relationship between them and hopefully guide our clinical
drug treatment of AAA. Here, we also analyzed some pharmacological inhibitors targeting
NLRP3 inflammasome or AIM2 inflammasome discovered in recent years and described
their mechanisms of action and therapeutic potential for experimental AAAs. While these
studies on AAA are mostly still at the drug discovery stage (candidate drug development),
these candidates have great potential for future in-depth research and even the treatment
of clinical AAA due to the lack of FDA (U.S. Food and Drug Administration)- or CFDA
(China Food and Drug Administration)-approved drug therapies to limit the progression
of AAA or reduce the risk of AAA rupture. In conclusion, we expect future studies to
pay more attention to demonstrating comprehensively and explicitly how the mechanisms
underlying inflammasome enhance the progression of AAA as well as explore the prospect
of treating clinical AAA via pharmacological inhibitors targeting inflammasome so that
certain potential ideal drugs can be developed and applied as soon as possible, although
no selective inhibitor of inflammasome has been approved for clinical treatment at present.

Author Contributions: Conceptualization, S.P. and S.X.; methodology, S.P., S.X. and Y.Y.; writing—original
draft preparation, S.P.; writing—review and editing, S.P., S.X., Y.Y. and H.D.; visualization, S.P. and S.X.;
supervision, H.D. All authors have read and agreed to the published version of the manuscript.
Funding: This work was funded by the Scientific Research Innovation Fund Project of Wuhan
Wuchang Hospital (no. WCYY2022Y03), the Fundamental Research Funds for the Central Universities
(no. 2042023kf0040), the Special Project of Central Government Guiding Local Science and Technology
Development in Hubei Province (no. 2020ZYYD002), and the Natural Science Foundation of Hubei
Province (no. 2023AFB256).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Special credit should be given to Xiaoxing Xiong for his visualization work to
improve the quality of this article.
Conflicts of Interest: The authors declare no conflicts of interest.

References
1. Lopez-Sanz, L.; Bernal, S.; Jimenez-Castilla, L.; Prieto, I.; La Manna, S.; Gomez-Lopez, S.; Blanco-Colio, L.M.; Egido, J.; Martin-
Ventura, J.L.; Gomez-Guerrero, C. Fcγ receptor activation mediates vascular inflammation and abdominal aortic aneurysm
development. Clin. Transl. Med. 2021, 11, e463. [CrossRef] [PubMed]
2. Golledge, J.; Thanigaimani, S.; Powell, J.T.; Tsao, P.S. Pathogenesis and management of abdominal aortic aneurysm. Eur. Heart J.
2023, 44, 2682–2697. [CrossRef] [PubMed]
3. Fenton, C.; Tan, A.R.; Abaraogu, U.O.; McCaslin, J.E. Prehabilitation exercise therapy before elective abdominal aortic aneurysm
repair. Cochrane Database Syst. Rev. 2021, 7, Cd013662. [CrossRef] [PubMed]
4. Baman, J.R.; Eskandari, M.K. What Is an Abdominal Aortic Aneurysm? JAMA 2022, 328, 2280. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2024, 25, 5001 13 of 17

5. Luebke, T.; Brunkwall, J. Risk-Adjusted Meta-analysis of 30-Day Mortality of Endovascular Versus Open Repair for Ruptured
Abdominal Aortic Aneurysms. Ann. Vasc. Surg. 2015, 29, 845–863. [CrossRef] [PubMed]
6. Longo, G.M.; Xiong, W.; Greiner, T.C.; Zhao, Y.; Fiotti, N.; Baxter, B.T. Matrix metalloproteinases 2 and 9 work in concert to
produce aortic aneurysms. J. Clin. Investig. 2002, 110, 625–632. [CrossRef] [PubMed]
7. Longo, G.M.; Buda, S.J.; Fiotta, N.; Xiong, W.; Griener, T.; Shapiro, S.; Baxter, B.T. MMP-12 has a role in abdominal aortic
aneurysms in mice. Surgery 2005, 137, 457–462. [CrossRef]
8. Kobeissi, E.; Hibino, M.; Pan, H.; Aune, D. Blood pressure, hypertension and the risk of abdominal aortic aneurysms: A systematic
review and meta-analysis of cohort studies. Eur. J. Epidemiol. 2019, 34, 547–555. [CrossRef] [PubMed]
9. Jacomelli, J.; Summers, L.; Stevenson, A.; Lees, T.; Earnshaw, J.J. Editor’s Choice—Inequalities in Abdominal Aortic Aneurysm
Screening in England: Effects of Social Deprivation and Ethnicity. Eur. J. Vasc. Endovasc. Surg. 2017, 53, 837–843. [CrossRef]
10. Aune, D.; Schlesinger, S.; Norat, T.; Riboli, E. Diabetes mellitus and the risk of abdominal aortic aneurysm: A systematic review
and meta-analysis of prospective studies. J. Diabetes Complicat. 2018, 32, 1169–1174. [CrossRef]
11. Chaikof, E.L.; Dalman, R.L.; Eskandari, M.K.; Jackson, B.M.; Lee, W.A.; Mansour, M.A.; Mastracci, T.M.; Mell, M.; Murad,
M.H.; Nguyen, L.L.; et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic
aneurysm. J. Vasc. Surg. 2018, 67, 2–77.e72. [CrossRef] [PubMed]
12. Wanhainen, A.; Verzini, F.; Van Herzeele, I.; Allaire, E.; Bown, M.; Cohnert, T.; Dick, F.; van Herwaarden, J.; Karkos, C.; Koelemay,
M.; et al. Editor’s Choice—European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of
Abdominal Aorto-iliac Artery Aneurysms. Eur. J. Vasc. Endovasc. Surg. 2019, 57, 8–93. [CrossRef]
13. Prinssen, M.; Verhoeven, E.L.; Buth, J.; Cuypers, P.W.; van Sambeek, M.R.; Balm, R.; Buskens, E.; Grobbee, D.E.; Blankensteijn,
J.D. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N. Engl. J. Med. 2004,
351, 1607–1618. [CrossRef]
14. Calero, A.; Illig, K.A. Overview of aortic aneurysm management in the endovascular era. Semin. Vasc. Surg. 2016, 29, 3–17.
[CrossRef] [PubMed]
15. Ersryd, S.; Djavani Gidlund, K.; Wanhainen, A.; Smith, L.; Björck, M. Editor’s Choice—Abdominal Compartment Syndrome after
Surgery for Abdominal Aortic Aneurysm: Subgroups, Risk Factors, and Outcome. Eur. J. Vasc. Endovasc. Surg. 2019, 58, 671–679.
[CrossRef]
16. Meijer, C.A.; Stijnen, T.; Wasser, M.N.; Hamming, J.F.; van Bockel, J.H.; Lindeman, J.H. Doxycycline for stabilization of abdominal
aortic aneurysms: A randomized trial. Ann. Intern. Med. 2013, 159, 815–823. [CrossRef] [PubMed]
17. Lamblin, N.; Ratajczak, P.; Hot, D.; Dubois, E.; Chwastyniak, M.; Beseme, O.; Drobecq, H.; Lemoine, Y.; Koussa, M.; Amouyel, P.;
et al. Profile of macrophages in human abdominal aortic aneurysms: A transcriptomic, proteomic, and antibody protein array
study. J. Proteome Res. 2010, 9, 3720–3729. [CrossRef]
18. Golledge, J. Abdominal aortic aneurysm: Update on pathogenesis and medical treatments. Nat. Rev. Cardiol. 2019, 16, 225–242.
[CrossRef]
19. Batra, R.; Suh, M.K.; Carson, J.S.; Dale, M.A.; Meisinger, T.M.; Fitzgerald, M.; Opperman, P.J.; Luo, J.; Pipinos, I.I.; Xiong, W.; et al.
IL-1β (Interleukin-1β) and TNF-α (Tumor Necrosis Factor-α) Impact Abdominal Aortic Aneurysm Formation by Differential
Effects on Macrophage Polarization. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 457–463. [CrossRef]
20. Johnston, W.F.; Salmon, M.; Su, G.; Lu, G.; Stone, M.L.; Zhao, Y.; Owens, G.K.; Upchurch, G.R., Jr.; Ailawadi, G. Genetic and
pharmacologic disruption of interleukin-1β signaling inhibits experimental aortic aneurysm formation. Arterioscler. Thromb. Vasc.
Biol. 2013, 33, 294–304. [CrossRef]
21. Martinon, F.; Burns, K.; Tschopp, J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and
processing of proIL-beta. Mol. Cell 2002, 10, 417–426. [CrossRef]
22. Netea, M.G.; van de Veerdonk, F.L.; van der Meer, J.W.; Dinarello, C.A.; Joosten, L.A. Inflammasome-independent regulation of
IL-1-family cytokines. Annu. Rev. Immunol. 2015, 33, 49–77. [CrossRef] [PubMed]
23. Jin, Y.; Fu, J. Novel Insights Into the NLRP 3 Inflammasome in Atherosclerosis. J. Am. Heart Assoc. 2019, 8, e012219. [CrossRef]
[PubMed]
24. Schroder, K.; Tschopp, J. The inflammasomes. Cell 2010, 140, 821–832. [CrossRef] [PubMed]
25. Awad, F.; Assrawi, E.; Louvrier, C.; Jumeau, C.; Georgin-Lavialle, S.; Grateau, G.; Amselem, S.; Giurgea, I.; Karabina, S.A.
Inflammasome biology, molecular pathology and therapeutic implications. Pharmacol. Ther. 2018, 187, 133–149. [CrossRef]
[PubMed]
26. Tschopp, J.; Schroder, K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?
Nat. Rev. Immunol. 2010, 10, 210–215. [CrossRef]
27. Latz, E. The inflammasome: From bench to bedside. Nat. Rev. Immunol. 2021, 21, 622–623. [CrossRef] [PubMed]
28. Sun, L.; Li, X.; Luo, Z.; Li, M.; Liu, H.; Zhu, Z.; Wang, J.; Lu, P.; Wang, L.; Yang, C.; et al. Purinergic receptor P2X7 contributes to
abdominal aortic aneurysm development via modulating macrophage pyroptosis and inflammation. Transl. Res. 2023, 258, 72–85.
[CrossRef] [PubMed]
29. Chen, M.Y.; Ye, X.J.; He, X.H.; Ouyang, D.Y. The Signaling Pathways Regulating NLRP3 Inflammasome Activation. Inflammation
2021, 44, 1229–1245. [CrossRef]
30. Wang, Y.; Gao, W.; Shi, X.; Ding, J.; Liu, W.; He, H.; Wang, K.; Shao, F. Chemotherapy drugs induce pyroptosis through caspase-3
cleavage of a gasdermin. Nature 2017, 547, 99–103. [CrossRef]
Int. J. Mol. Sci. 2024, 25, 5001 14 of 17

31. Shi, J.; Gao, W.; Shao, F. Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. Trends Biochem. Sci. 2017, 42, 245–254.
[CrossRef] [PubMed]
32. Zhang, D.; Yan, H.; Hu, Y.; Zhuang, Z.; Yu, Z.; Hang, C. Increased Expression of NLRP3 Inflammasome in Wall of Ruptured and
Unruptured Human Cerebral Aneurysms: Preliminary Results. J. Stroke Cerebrovasc. Dis. 2015, 24, 972–979. [CrossRef] [PubMed]
33. Wu, D.; Zheng, Y.; Choi, J.C.; Zhang, L.; Coselli, J.S.; Shen, Y.H.; LeMaire, S.A. Blockade of the NLRP3 Inflammasome Cascade
Prevents Thoracic Aortic Aneurysm and Dissection Formation. J. Surg. Res. 2014, 186, 521–522. [CrossRef]
34. Fu, J.; Wu, H. Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation. Annu. Rev. Immunol. 2023, 41, 301–316.
[CrossRef]
35. Ma, Q. Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interac-
tion. Pharmacol. Rev. 2023, 75, 487–520. [CrossRef] [PubMed]
36. Liu, X.; Zhang, Z.; Ruan, J.; Pan, Y.; Magupalli, V.G.; Wu, H.; Lieberman, J. Inflammasome-activated gasdermin D causes
pyroptosis by forming membrane pores. Nature 2016, 535, 153–158. [CrossRef] [PubMed]
37. Booshehri, L.M.; Hoffman, H.M. CAPS and NLRP3. J. Clin. Immunol. 2019, 39, 277–286. [CrossRef] [PubMed]
38. Putnam, C.D.; Broderick, L.; Hoffman, H.M. The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes
and innate immunity. Immunol. Rev. 2024, 322, 259–282. [CrossRef]
39. Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.C.;
et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013, 493, 674–678.
[CrossRef]
40. Yin, H.; Liu, N.; Sigdel, K.R.; Duan, L. Role of NLRP3 Inflammasome in Rheumatoid Arthritis. Front. Immunol. 2022, 13, 931690.
[CrossRef]
41. Guo, H.; Callaway, J.B.; Ting, J.P. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat. Med. 2015,
21, 677–687. [CrossRef] [PubMed]
42. Roberts, R.L.; Van Rij, A.M.; Phillips, L.V.; Young, S.; McCormick, S.P.; Merriman, T.R.; Jones, G.T. Interaction of the inflammasome
genes CARD8 and NLRP3 in abdominal aortic aneurysms. Atherosclerosis 2011, 218, 123–126. [CrossRef] [PubMed]
43. Usui, F.; Shirasuna, K.; Kimura, H.; Tatsumi, K.; Kawashima, A.; Karasawa, T.; Yoshimura, K.; Aoki, H.; Tsutsui, H.; Noda, T.; et al.
Inflammasome activation by mitochondrial oxidative stress in macrophages leads to the development of angiotensin II-induced
aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 127–136. [CrossRef]
44. Wu, D.; Ren, P.; Zheng, Y.; Zhang, L.; Xu, G.; Xie, W.; Lloyd, E.E.; Zhang, S.; Zhang, Q.; Curci, J.A.; et al. NLRP3 (Nucleotide
Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3)-Caspase-1 Inflammasome Degrades Contractile
Proteins: Implications for Aortic Biomechanical Dysfunction and Aneurysm and Dissection Formation. Arterioscler. Thromb. Vasc.
Biol. 2017, 37, 694–706. [CrossRef] [PubMed]
45. Ren, P.; Wu, D.; Appel, R.; Zhang, L.; Zhang, C.; Luo, W.; Robertson, A.A.B.; Cooper, M.A.; Coselli, J.S.; Milewicz, D.M.; et al.
Targeting the NLRP3 Inflammasome with Inhibitor MCC950 Prevents Aortic Aneurysms and Dissections in Mice. J. Am. Heart
Assoc. 2020, 9, e014044. [CrossRef] [PubMed]
46. Sun, W.; Pang, Y.; Liu, Z.; Sun, L.; Liu, B.; Xu, M.; Dong, Y.; Feng, J.; Jiang, C.; Kong, W.; et al. Macrophage inflammasome
mediates hyperhomocysteinemia-aggravated abdominal aortic aneurysm. J. Mol. Cell. Cardiol. 2015, 81, 96–106. [CrossRef]
[PubMed]
47. Filiberto, A.C.; Spinosa, M.D.; Elder, C.T.; Su, G.; Leroy, V.; Ladd, Z.; Lu, G.; Mehaffey, J.H.; Salmon, M.D.; Hawkins, R.B.;
et al. Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm
formation. Nat. Commun. 2022, 13, 1521. [CrossRef]
48. DeYoung, K.L.; Ray, M.E.; Su, Y.A.; Anzick, S.L.; Johnstone, R.W.; Trapani, J.A.; Meltzer, P.S.; Trent, J.M. Cloning a novel member of
the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene
1997, 15, 453–457. [CrossRef]
49. Hornung, V.; Ablasser, A.; Charrel-Dennis, M.; Bauernfeind, F.; Horvath, G.; Caffrey, D.R.; Latz, E.; Fitzgerald, K.A. AIM2
recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2009, 458, 514–518. [CrossRef]
50. Fernandes-Alnemri, T.; Yu, J.W.; Datta, P.; Wu, J.; Alnemri, E.S. AIM2 activates the inflammasome and cell death in response to
cytoplasmic DNA. Nature 2009, 458, 509–513. [CrossRef]
51. Hakimi, M.; Peters, A.; Becker, A.; Böckler, D.; Dihlmann, S. Inflammation-related induction of absent in melanoma 2 (AIM2) in
vascular cells and atherosclerotic lesions suggests a role in vascular pathogenesis. J. Vasc. Surg. 2014, 59, 794–803. [CrossRef]
[PubMed]
52. Qi, M.; Dai, D.; Liu, J.; Li, Z.; Liang, P.; Wang, Y.; Cheng, L.; Zhan, Y.; An, Z.; Song, Y.; et al. AIM2 promotes the development of
non-small cell lung cancer by modulating mitochondrial dynamics. Oncogene 2020, 39, 2707–2723. [CrossRef]
53. Wang, L.; Sun, L.; Byrd, K.M.; Ko, C.C.; Zhao, Z.; Fang, J. AIM2 Inflammasome’s First Decade of Discovery: Focus on Oral
Diseases. Front. Immunol. 2020, 11, 1487. [CrossRef] [PubMed]
54. Flynn, R.L.; Zou, L. Oligonucleotide/oligosaccharide-binding fold proteins: A growing family of genome guardians. Crit. Rev.
Biochem. Mol. Biol. 2010, 45, 266–275. [CrossRef] [PubMed]
55. Zhao, Z.Z.; Zheng, X.L.; Jiang, Z.S. Emerging roles of absent in melanoma 2 in cardiovascular diseases. Clin. Chim. Acta 2020,
511, 14–23. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2024, 25, 5001 15 of 17

56. Fu, R.; Zhao, L.; Guo, Y.; Qin, X.; Xu, W.; Cheng, X.; Zhang, Y.; Xu, S. AIM2 inflammasome: A potential therapeutic target in
ischemic stroke. Clin. Immunol. 2024, 259, 109881. [CrossRef]
57. Cunha, L.D.; Silva, A.L.N.; Ribeiro, J.M.; Mascarenhas, D.P.A.; Quirino, G.F.S.; Santos, L.L.; Flavell, R.A.; Zamboni, D.S. AIM2
Engages Active but Unprocessed Caspase-1 to Induce Noncanonical Activation of the NLRP3 Inflammasome. Cell Rep. 2017,
20, 794–805. [CrossRef]
58. Dihlmann, S.; Erhart, P.; Mehrabi, A.; Nickkholgh, A.; Lasitschka, F.; Böckler, D.; Hakimi, M. Increased expression and activation
of absent in melanoma 2 inflammasome components in lymphocytic infiltrates of abdominal aortic aneurysms. Mol. Med. 2014,
20, 230–237. [CrossRef]
59. Wortmann, M.; Xiao, X.; Wabnitz, G.; Samstag, Y.; Hakimi, M.; Böckler, D.; Dihlmann, S. AIM2 levels and DNA-triggered
inflammasome response are increased in peripheral leukocytes of patients with abdominal aortic aneurysm. Inflamm. Res. 2019,
68, 337–345. [CrossRef]
60. Wu, X.; Cakmak, S.; Wortmann, M.; Hakimi, M.; Zhang, J.; Böckler, D.; Dihlmann, S. Sex- and disease-specific inflammasome
signatures in circulating blood leukocytes of patients with abdominal aortic aneurysm. Mol. Med. 2016, 22, 505–518. [CrossRef]
61. Canonico, M.E.; Piccolo, R.; Avvedimento, M.; Leone, A.; Esposito, S.; Franzone, A.; Giugliano, G.; Gargiulo, G.; Hess, C.N.;
Berkowitz, S.D.; et al. Antithrombotic Therapy in Peripheral Artery Disease: Current Evidence and Future Directions. J. Cardiovasc.
Dev. Dis. 2023, 10, 164. [CrossRef] [PubMed]
62. Golledge, J.; Norman, P.E. Atherosclerosis and abdominal aortic aneurysm: Cause, response, or common risk factors? Arterioscler.
Thromb. Vasc. Biol. 2010, 30, 1075–1077. [CrossRef] [PubMed]
63. Takahashi, M. NLRP3 Inflammasome as a Common Denominator of Atherosclerosis and Abdominal Aortic Aneurysm. Circ. J.
2021, 85, 2129–2136. [CrossRef] [PubMed]
64. Duewell, P.; Kono, H.; Rayner, K.J.; Sirois, C.M.; Vladimer, G.; Bauernfeind, F.G.; Abela, G.S.; Franchi, L.; Nuñez, G.; Schnurr, M.;
et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010, 464, 1357–1361.
[CrossRef] [PubMed]
65. Karasawa, T.; Takahashi, M. The crystal-induced activation of NLRP3 inflammasomes in atherosclerosis. Inflamm. Regen. 2017, 37, 18.
[CrossRef] [PubMed]
66. Usui, F.; Shirasuna, K.; Kimura, H.; Tatsumi, K.; Kawashima, A.; Karasawa, T.; Hida, S.; Sagara, J.; Taniguchi, S.; Takahashi, M.
Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein
E-deficient mice. Biochem. Biophys. Res. Commun. 2012, 425, 162–168. [CrossRef]
67. Karasawa, T.; Kawashima, A.; Usui-Kawanishi, F.; Watanabe, S.; Kimura, H.; Kamata, R.; Shirasuna, K.; Koyama, Y.;
Sato-Tomita, A.; Matsuzaka, T.; et al. Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3
Inflammasome in Macrophages. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 744–756. [CrossRef]
68. Peng, K.; Liu, L.; Wei, D.; Lv, Y.; Wang, G.; Xiong, W.; Wang, X.; Altaf, A.; Wang, L.; He, D.; et al. P2X7R is involved in the
progression of atherosclerosis by promoting NLRP3 inflammasome activation. Int. J. Mol. Med. 2015, 35, 1179–1188. [CrossRef]
69. Folco, E.J.; Sukhova, G.K.; Quillard, T.; Libby, P. Moderate hypoxia potentiates interleukin-1β production in activated human
macrophages. Circ. Res. 2014, 115, 875–883. [CrossRef]
70. Tumurkhuu, G.; Shimada, K.; Dagvadorj, J.; Crother, T.R.; Zhang, W.; Luthringer, D.; Gottlieb, R.A.; Chen, S.; Arditi, M.
Ogg1-Dependent DNA Repair Regulates NLRP3 Inflammasome and Prevents Atherosclerosis. Circ. Res. 2016, 119, e76–e90.
[CrossRef]
71. Shi, J.; Guo, J.; Li, Z.; Xu, B.; Miyata, M. Importance of NLRP3 Inflammasome in Abdominal Aortic Aneurysms. J. Atheroscler.
Thromb. 2021, 28, 454–466. [CrossRef] [PubMed]
72. Li, Y.; Xia, Y.; Yin, S.; Wan, F.; Hu, J.; Kou, L.; Sun, Y.; Wu, J.; Zhou, Q.; Huang, J.; et al. Targeting Microglial α-Synuclein/TLRs/NF-
kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease. Front. Immunol. 2021, 12, 719807. [CrossRef]
73. Yuan, Z.; Lu, Y.; Wei, J.; Wu, J.; Yang, J.; Cai, Z. Abdominal Aortic Aneurysm: Roles of Inflammatory Cells. Front. Immunol. 2020,
11, 609161. [CrossRef]
74. Shridas, P.; De Beer, M.C.; Webb, N.R. High-density lipoprotein inhibits serum amyloid A-mediated reactive oxygen species
generation and NLRP3 inflammasome activation. J. Biol. Chem. 2018, 293, 13257–13269. [CrossRef]
75. Shridas, P.; Patrick, A.C.; Tannock, L.R. Role of Serum Amyloid A in Abdominal Aortic Aneurysm and Related Cardiovascular
Diseases. Biomolecules 2021, 11, 1883. [CrossRef]
76. Kelley, N.; Jeltema, D.; Duan, Y.; He, Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation.
Int. J. Mol. Sci. 2019, 20, 3328. [CrossRef]
77. Hooftman, A.; Angiari, S.; Hester, S.; Corcoran, S.E.; Runtsch, M.C.; Ling, C.; Ruzek, M.C.; Slivka, P.F.; McGettrick, A.F.; Banahan,
K.; et al. The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation. Cell Metab. 2020,
32, 468–478.e467. [CrossRef] [PubMed]
78. Chen, J.; Chen, Z.J. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature 2018, 564, 71–76.
[CrossRef] [PubMed]
79. McKee, C.M.; Coll, R.C. NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma. J. Leukoc. Biol. 2020,
108, 937–952. [CrossRef]
80. Karasawa, T.; Kawashima, A.; Usui, F.; Kimura, H.; Shirasuna, K.; Inoue, Y.; Komada, T.; Kobayashi, M.; Mizushina, Y.; Sagara, J.;
et al. Oligomerized CARD16 promotes caspase-1 assembly and IL-1β processing. FEBS Open Bio 2015, 5, 348–356. [CrossRef]
Int. J. Mol. Sci. 2024, 25, 5001 16 of 17

81. Kawashima, A.; Karasawa, T.; Tago, K.; Kimura, H.; Kamata, R.; Usui-Kawanishi, F.; Watanabe, S.; Ohta, S.; Funakoshi-Tago, M.;
Yanagisawa, K.; et al. ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages.
J. Immunol. 2017, 199, 3614–3622. [CrossRef] [PubMed]
82. Takahashi, M. NLRP3 inflammasome as a key driver of vascular disease. Cardiovasc. Res. 2022, 118, 372–385. [CrossRef] [PubMed]
83. Erhart, P.; Cakmak, S.; Grond-Ginsbach, C.; Hakimi, M.; Böckler, D.; Dihlmann, S. Inflammasome activity in leucocytes decreases
with abdominal aortic aneurysm progression. Int. J. Mol. Med. 2019, 44, 1299–1308. [CrossRef]
84. Bambouskova, M.; Potuckova, L.; Paulenda, T.; Kerndl, M.; Mogilenko, D.A.; Lizotte, K.; Swain, A.; Hayes, S.; Sheldon, R.D.; Kim,
H.; et al. Itaconate confers tolerance to late NLRP3 inflammasome activation. Cell Rep. 2021, 34, 108756. [CrossRef] [PubMed]
85. Wortmann, M.; Skorubskaya, E.; Peters, A.S.; Hakimi, M.; Böckler, D.; Dihlmann, S. Necrotic cell debris induces a NF-κB-driven
inflammasome response in vascular smooth muscle cells derived from abdominal aortic aneurysms (AAA-SMC). Biochem. Biophys.
Res. Commun. 2019, 511, 343–349. [CrossRef] [PubMed]
86. Ridker, P.M.; Everett, B.M.; Thuren, T.; MacFadyen, J.G.; Chang, W.H.; Ballantyne, C.; Fonseca, F.; Nicolau, J.; Koenig, W.;
Anker, S.D.; et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N. Engl. J. Med. 2017, 377,
1119–1131. [CrossRef]
87. Coll, R.C.; Hill, J.R.; Day, C.J.; Zamoshnikova, A.; Boucher, D.; Massey, N.L.; Chitty, J.L.; Fraser, J.A.; Jennings, M.P.;
Robertson, A.A.B.; et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat. Chem. Biol.
2019, 15, 556–559. [CrossRef] [PubMed]
88. Lamkanfi, M.; Mueller, J.L.; Vitari, A.C.; Misaghi, S.; Fedorova, A.; Deshayes, K.; Lee, W.P.; Hoffman, H.M.; Dixit, V.M. Glyburide
inhibits the Cryopyrin/Nalp3 inflammasome. J. Cell Biol. 2009, 187, 61–70. [CrossRef]
89. Huang, Y.; Jiang, H.; Chen, Y.; Wang, X.; Yang, Y.; Tao, J.; Deng, X.; Liang, G.; Zhang, H.; Jiang, W.; et al. Tranilast directly targets
NLRP3 to treat inflammasome-driven diseases. EMBO Mol. Med. 2018, 10, e8689. [CrossRef]
90. Zahid, A.; Li, B.; Kombe, A.J.K.; Jin, T.; Tao, J. Pharmacological Inhibitors of the NLRP3 Inflammasome. Front. Immunol. 2019,
10, 2538. [CrossRef]
91. Tsuruda, T.; Kato, J.; Hatakeyama, K.; Kojima, K.; Yano, M.; Yano, Y.; Nakamura, K.; Nakamura-Uchiyama, F.; Matsushima, Y.;
Imamura, T.; et al. Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm. Circ. Res.
2008, 102, 1368–1377. [CrossRef]
92. Ren, J.; Han, Y.; Ren, T.; Fang, H.; Xu, X.; Lun, Y.; Jiang, H.; Xin, S.; Zhang, J. AEBP1 Promotes the Occurrence and Development
of Abdominal Aortic Aneurysm by Modulating Inflammation via the NF-κB Pathway. J. Atheroscler. Thromb. 2020, 27, 255–270.
[CrossRef] [PubMed]
93. Juliana, C.; Fernandes-Alnemri, T.; Wu, J.; Datta, P.; Solorzano, L.; Yu, J.W.; Meng, R.; Quong, A.A.; Latz, E.; Scott, C.P.; et al.
Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J. Biol. Chem. 2010,
285, 9792–9802. [CrossRef] [PubMed]
94. Ren, J.; Liu, Z.; Wang, Q.; Giles, J.; Greenberg, J.; Sheibani, N.; Kent, K.C.; Liu, B. Andrographolide Ameliorates Abdominal Aortic
Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression.
J. Pharmacol. Exp. Ther. 2016, 356, 137–147. [CrossRef] [PubMed]
95. Gao, J.; Peng, S.; Shan, X.; Deng, G.; Shen, L.; Sun, J.; Jiang, C.; Yang, X.; Chang, Z.; Sun, X.; et al. Inhibition of AIM2 inflammasome-
mediated pyroptosis by Andrographolide contributes to amelioration of radiation-induced lung inflammation and fibrosis. Cell
Death Dis. 2019, 10, 957. [CrossRef] [PubMed]
96. Wang, L.; Wang, B.; Li, H.; Lu, H.; Qiu, F.; Xiong, L.; Xu, Y.; Wang, G.; Liu, X.; Wu, H.; et al. Quercetin, a flavonoid with anti-
inflammatory activity, suppresses the development of abdominal aortic aneurysms in mice. Eur. J. Pharmacol. 2012, 690, 133–141.
[CrossRef] [PubMed]
97. Domiciano, T.P.; Wakita, D.; Jones, H.D.; Crother, T.R.; Verri, W.A., Jr.; Arditi, M.; Shimada, K. Quercetin Inhibits Inflammasome
Activation by Interfering with ASC Oligomerization and Prevents Interleukin-1 Mediated Mouse Vasculitis. Sci. Rep. 2017,
7, 41539. [CrossRef]
98. Mangan, M.S.J.; Olhava, E.J.; Roush, W.R.; Seidel, H.M.; Glick, G.D.; Latz, E. Targeting the NLRP3 inflammasome in inflammatory
diseases. Nat. Rev. Drug Discov. 2018, 17, 688. [CrossRef] [PubMed]
99. Perregaux, D.G.; McNiff, P.; Laliberte, R.; Hawryluk, N.; Peurano, H.; Stam, E.; Eggler, J.; Griffiths, R.; Dombroski, M.A.; Gabel,
C.A. Identification and characterization of a novel class of interleukin-1 post-translational processing inhibitors. J. Pharmacol. Exp.
Ther. 2001, 299, 187–197.
100. Coll, R.C.; Robertson, A.A.; Chae, J.J.; Higgins, S.C.; Muñoz-Planillo, R.; Inserra, M.C.; Vetter, I.; Dungan, L.S.; Monks, B.G.; Stutz,
A.; et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 2015,
21, 248–255. [CrossRef]
101. Ashcroft, F.M. ATP-sensitive potassium channelopathies: Focus on insulin secretion. J. Clin. Investig. 2005, 115, 2047–2058.
[CrossRef] [PubMed]
102. Platten, M.; Ho, P.P.; Youssef, S.; Fontoura, P.; Garren, H.; Hur, E.M.; Gupta, R.; Lee, L.Y.; Kidd, B.A.; Robinson, W.H.; et al.
Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science 2005, 310, 850–855. [CrossRef]
[PubMed]
103. Li, N.; Wang, Y.; Wang, X.; Sun, N.; Gong, Y.H. Pathway network of pyroptosis and its potential inhibitors in acute kidney injury.
Pharmacol. Res. 2022, 175, 106033. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2024, 25, 5001 17 of 17

104. Kerr, I.D.; Lee, J.H.; Farady, C.J.; Marion, R.; Rickert, M.; Sajid, M.; Pandey, K.C.; Caffrey, C.R.; Legac, J.; Hansell, E.; et al. Vinyl
sulfones as antiparasitic agents and a structural basis for drug design. J. Biol. Chem. 2009, 284, 25697–25703. [CrossRef] [PubMed]
105. Zhang, H.; Li, S.; Si, Y.; Xu, H. Andrographolide and its derivatives: Current achievements and future perspectives. Eur. J. Med.
Chem. 2021, 224, 113710. [CrossRef]
106. Han, X.; Xu, T.; Fang, Q.; Zhang, H.; Yue, L.; Hu, G.; Sun, L. Quercetin hinders microglial activation to alleviate neurotoxicity via
the interplay between NLRP3 inflammasome and mitophagy. Redox Biol. 2021, 44, 102010. [CrossRef] [PubMed]
107. Sul, O.J.; Ra, S.W. Quercetin Prevents LPS-Induced Oxidative Stress and Inflammation by Modulating NOX2/ROS/NF-kB in
Lung Epithelial Cells. Molecules 2021, 26, 6949. [CrossRef]
108. Liu, X.; Tao, T.; Yao, H.; Zheng, H.; Wang, F.; Gao, Y. Mechanism of action of quercetin in rheumatoid arthritis models: Meta-
analysis and systematic review of animal studies. Inflammopharmacology 2023, 31, 1629–1645. [CrossRef]

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