Hindawi

Mediators of Inflammation
Volume 2023, Article ID 8821610, 20 pages
https://doi.org/10.1155/2023/8821610

Review Article
Regulatory Mechanism of M1/M2 Macrophage Polarization in the
Development of Autoimmune Diseases

Yuan Peng ,1 Mengxian Zhou ,1 Hong Yang ,2 Ruyi Qu ,1 Yan Qiu ,3 Jiawen Hao ,1
Hongsheng Bi ,4 and Dadong Guo 4
1
Shandong University of Traditional Chinese Medicine, Jinan 250002, China
2
Qingdao Traditional Chinese Medicine Hospital (Qingdao Hiser Hospital), Qingdao 266033, China
3
The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250002, China
4
Shandong Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Therapy of
Ocular Diseases; Shandong Academy of Eye Disease Prevention and Therapy, Medical College of Optometry and Ophthalmology,
Shandong University of Traditional Chinese Medicine, Jinan 250002, China

Correspondence should be addressed to Dadong Guo; [email protected]

Received 20 January 2023; Revised 21 April 2023; Accepted 23 May 2023; Published 8 June 2023

Academic Editor: Paola Migliorini

Copyright © 2023 Yuan Peng et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Macrophages are innate immune cells in the organism and can be found in almost tissues and organs. They are highly plastic and
heterogeneous cells and can participate in the immune response, thereby playing a crucial role in maintaining the immune
homeostasis of the body. It is well known that undifferentiated macrophages can polarize into classically activated
macrophages (M1 macrophages) and alternatively activated macrophages (M2 macrophages) under different
microenvironmental conditions. The directions of macrophage polarization can be regulated by a series of factors, including
interferon, lipopolysaccharide, interleukin, and noncoding RNAs. To elucidate the role of macrophages in various autoimmune
diseases, we searched the literature on macrophages with the PubMed database. Search terms are as follows: macrophages,
polarization, signaling pathways, noncoding RNA, inflammation, autoimmune diseases, systemic lupus erythematosus,
rheumatoid arthritis, lupus nephritis, Sjogren’s syndrome, Guillain-Barré syndrome, and multiple sclerosis. In the present
study, we summarize the role of macrophage polarization in common autoimmune diseases. In addition, we also summarize
the features and recent advances with a particular focus on the immunotherapeutic potential of macrophage polarization in
autoimmune diseases and the potentially effective therapeutic targets.

1. Introduction gens, produce excess autoantibodies against antigens, over-

respond to immune cells, attack its tissues and organs, and
Autoimmune diseases are chronic, refractory clinical com- cause cell damage or abnormal function, resulting in local
mon diseases that are mainly stimulated by immune, hor- or systemic inflammation and tissue damage [3]. Autoanti-
monal, environmental, and genetic factors [1]. To date, gens may include viruses, abnormally deposited immune
there are approximately 150 autoimmune diseases, and the complexes, extra neutrophil traps, or excess apoptotic sub-
prevalence is increasing year by year. Clinically, most auto- stances [4]. Macrophages are an essential part of the innate
immune diseases are chronic that exist for a long time or immune system, which exists in almost all body tissues, con-
even accompany patients for life, and there is still no specific tribute to immune regulation and tissue repair, and maintain
treatment method [2]. Autoimmune diseases seriously affect immune homeostasis [5]. Macrophages are the dominant
patients’ health, so it is urgent to find effective treatment immune cell population at all disease stages, and their dys-
strategies to improve their quality of life. However, the path- function can lead to abnormal repair and regeneration, with
ogenesis of at least half of autoimmune diseases is unclear. runaway production of inflammatory mediators and growth
The immune system is believed to lose tolerance to autoanti- factors [6].
2 Mediators of Inflammation

Clear and convincing evidence has shown that 3. Results and Discussion
macrophages are highly plastic and can polarize into differ-
ent types of macrophages under different microenvironment 3.1. Origin and Function of Macrophages. In 1908, Nobel
conditions: classically activated macrophages (M1) and Prize winner Ilya Metchnikov discovered cells with phagocy-
alternatively activated macrophages (M2), a traditional clas- tosis from single-celled organisms to vertebrates and called
sification, and a simplified, old classification method. them macrophages [20]. Throughout life, the primary role
Among them, we prefer to interpret M2-type macrophages of macrophages is to phagocytose cell debris and recycle
as activated macrophages other than M1. M1 can be stimu- red blood cells damaged by aging, which is also linked to
lated and activated by lipopolysaccharide (LPS) and inter- iron metabolism [21]. Initially, there was a certain misun-
feron- (IFN-) γ; can secrete inflammatory factors such as derstanding about the origin of macrophages, and it was
tumor necrosis factor-α (TNF-α), interleukin(IL)-1β, and believed that macrophages could be continuously replen-
IL-6; and can generate a large number of reactive oxygen ished entirely by monocytes. Subsequently, researchers
species (ROS) and reactive nitrogen species (RNS), killing believe that there are two primary sources of macrophages:
invading pathogens, phagocytose, and clear senescent, dam- the first source is that monocytes originating from bone
aged, and degenerated cells [7, 8]. M2 can be activated by IL- marrow hematopoietic stem cells enter the tissue to form
4 and IL-13; can secrete anti-inflammatory cytokines includ- macrophages; the second source is the progenitor cells of
ing IL-10, IL-4, and transforming growth factor-β (TGF-β); the embryonic yolk sac, which develop into tissue-resident
can also produce vascular endothelial growth factor (VEGF) macrophages with local self-renewal capacity and exist inde-
and platelet-derived growth factor (PDGF); can inhibit T pendently of monocytes in adulthood [22–27]. As a type of
cell proliferation and activation; and can participate in T phagic cell, macrophages in the immune system can engulf
helper (Th) 2-type immunity response, contributing to tis- and kill foreign bacteria, pathogens, and cells damaged by
sue repair and angiogenesis [9, 10]. However, the excessive self-aging, participating in the body’s second line of defense.
accumulation of M2 macrophages is closely related to fibro- At the same time, macrophages can participate in antigen
sis [11]. Fibrosis results from excessive accumulation of processing and presentation, activating humoral immunity
extracellular matrix (ECM) components such as collagen and cellular immunity to initiate an adaptive immune
and fibronectin in dysregulated tissue repair after injury response [28]. As a result, macrophages can resist pathogen
[12]. ECM can promote wound healing and tissue repair attacks and play an essential role in the transmission of
when minor tissue damage occurs. By contrast, if the injury immune information, tissue development, and in maintain-
is severe, excessive accumulation of ECM can destroy tissue ing the body’s homeostasis.
structure and lead to organ dysfunction [12]. Thus, macro-
phages play an essential role in the development of fibrosis 3.2. Tissue Distribution of Macrophages. According to the
[13], of which M2a macrophages can significantly promote distribution of different physiological locations, macro-
fibrosis progression [14]. phages are mainly found in lymph nodes, alveolar walls,
Macrophage polarization is a dynamic and reversible bone marrow, liver, spleen, and other organs. They can be
process involved in the occurrence and development of divided into subgroups, including microglia in the central
many autoimmune diseases, such as uveitis, systemic lupus nervous system, osteoclasts, alveolar macrophages in the
erythematosus, rheumatoid arthritis, and Sjogren’s syn- lung, histiocytes in the spleen and interstitial connective tis-
drome [15–19]. Studies have revealed that regulating the sue, and Kupffer cells in the liver [26]. Macrophages in dif-
balance of M1/M2 macrophage polarization can control ferent parts are closely related to diseases in corresponding
the inflammatory progression of autoimmune diseases, organs. For example, Kupffer cells in the hepatic sinuses
exhibiting an excellent therapeutic effect on alleviating can renew themselves and play a central role in acute and
inflammatory damage and helping extracellular matrix chronic liver failure, liver fibrosis, nonalcoholic fatty liver
remodeling in autoimmune diseases. This review mainly disease, alcoholic liver disease, viral hepatitis, and hepatocel-
describes the role of macrophage polarization and the lular carcinoma pathogenesis, as well as disease remission
research progress of polarized macrophages as therapeutic [10]. The central nervous system (CNS) microglia can influ-
targets in autoimmune diseases. ence neuronal postinjury properties by regulating the clear-
ance of myelin and cell debris and cytokine release [29].
2. Materials and Methodology Zabala et al. reported that blocking microglial P2X4 signal-
ing can exacerbate the clinical symptoms of experimental
A search strategy was performed to extract the available lit- autoimmune meningitis models, thereby contributing to
erature using the PubMed database. The search terms “mac- microglial activation into a proinflammatory phenotype [30].
rophages,” “polarization,” “signaling pathways,” “noncoding
RNA,” and “inflammation” combined with terms like auto-
immune diseases such as systemic lupus erythematosus, 3.3. Metabolic Characteristics of Macrophages. Shifts in cellu-
rheumatoid arthritis, lupus nephritis, Sjogren’s syndrome, lar metabolism are closely related to phenotypic and func-
Guillain-Barre syndrome, and multiple sclerosis were tional changes in macrophages. M1-type macrophage
searched. Original researches, including prospective and ret- metabolism mainly depends on glycolysis, followed by the
rospective studies and review papers, were included and pentose phosphate pathway (PPP), truncated tricarboxylic
cross-referenced. acid cycle (TCA cycle), and dysfunctional mitochondrial
Mediators of Inflammation 3

oxidative phosphorylation (OXPHOS) [31]. In contrast, M2 extreme classification method, it is still being used for the
cells depend more on OXPHOS and the TCA cycle because convenience of distinction, which is not a strict functional
their TCA cycle is intact and can provide substrates for the classification, but a simplified operating concept [25, 41].
electron transport chain (ETC) complex [32]. Recent The detailed subtypes and functions of M2 macrophages
advances in research have focused mainly on amino acids are also distinguished below. It is clear that LPS, IFN-γ,
and related metabolic pathways that promote macrophage TNF-α, and granulocyte-macrophage colony-stimulating
polarization, such as iNOS/ARG1 (arginine 1), the TCA factor (GM-CSF) stimulation activate M1 macrophages
cycle and OXPHOS (glutamine), and single-carbon metabo- (M1 biomarkers: CD86, CD40, and CD38) [42], and M1
lism (serine and glycine) [33]. Mitochondrial metabolism is macrophages secrete proinflammatory factors such as IL-
critically linked to macrophage polarization. Mitochondria 12, IL-6, IL-1β, IL-23, IFN-γ, and TNF-α, producing a large
provide energy for cells and coordinate signal transduction, number of ROS and inducible nitric oxide synthase (iNOS)
chromatin regulation, and transcriptional regulation to [43–45]. Therefore, they can promote the inflammatory
influence macrophage polarization by fine-tuning the response, resist pathogens, and inhibit the occurrence and
dynamic signals of the immune response [34]. So, we specu- development of tumors [46, 47]. Prostaglandins E2
late that those factors influencing macrophage metabolism (PGE2), IL-13, IL-4, and macrophage colony-stimulating
may disrupt M1/M2 homeostasis and exacerbate inflamma- factor (M-CSF) can activate M2 macrophages (M2 biomark-
tion. It has been shown that mitochondrial functional ers: CCL7, CCL17, CCL22, CCL24, CD83, and CD44 [48,
impairment can promote reactive oxygen species (ROS) pro- 49]. In addition, M2 macrophages can also inhibit the
duction, increase hypoxia-inducible factor 1-α (HIF1-α) inflammatory response and promote tissue remodeling and
expression, and decrease mitochondrial complexes I and IV tumor progression by producing anti-inflammatory factor
of OXPHOS, which in turn affect the reprogramming of mac- IL-10, transforming growth factor-β (TGF-β), peroxisome
rophages in glucose metabolism [35]. Therefore, it is meaning- proliferator-activated receptor γ (PPARγ), arginase 1
ful to focus on the role of glucose metabolism reprogramming (Arg1), Fizz1, and Ym1 [9, 50–52]. M2 macrophages pro-
of M1 macrophages in inflammatory initiation and to inhibit duce transcriptional changes under different stimulation
inflammation by blocking glucose metabolism reprogram- conditions, which can be subdivided into M2a, M2b, M2c,
ming. Researchers have identified a novel role in macrophage and M2d (Table 1).
activation-related inflammation, where metabolic reprogram- M2a induced by IL-4 and IL-13 is called wound healing
ming occurs after macrophage exposure to inflammatory macrophage, which highly expresses CD206, IL-1R, and
stimuli [36]. Itaconate, a mitochondrial metabolite in meta- CCL17 and secretes fibronectin and other fibrogenic mole-
bolic reprogramming, can inhibit succinate dehydrogenase cules, promoting tissue repair and remodeling [45, 53–56].
and multiple levels of glycolysis, activate anti-inflammatory Immune complexes, toll-like receptor (TLR) agonists, and
transcription factors nuclear factor E2-related factor 2 (Nrf2) IL-1R stimulate the production of M2b (regulating macro-
and activating transcription factor 3 (ATF3), and inhibit phages) that highly express CCL1 and TNFSF14. M2b can
NLR family pyrin domain containing 3 (NLRP3) inflamma- secrete anti-inflammatory and proinflammatory factors,
some [36–38]. Accordingly, the production of proinflamma- mainly involved in immune regulation and Th2 activation
tory mediators of M1 macrophages under LPS stimulation [45, 54–58]. Glucocorticoids, TGF-β, and IL-10 can induce
can be significantly reduced, damage can be ameliorated, and the production of M2c, which is characterized by CD163
tissue repair can be promoted [36]. on the surface and secretes IL-10 and TGF-β1 and participates
in inhibiting the immune response and tissue remodeling [45,
3.4. Macrophage Polarization. Mature macrophages undergo 55, 56, 58, 59]. TLR, adenosine receptor, and IL-6-induced
phenotypic and morphological differentiation under various M2d (tumor-associated macrophages) play a significant role
factors (e.g., pathogen invasion, tissue damage, and meta- in angiogenesis and tumor-related progression [45, 55, 56,
bolic disturbances) and termed macrophage polarization. 60–64]. However, studies have also found that in mouse
In the early stage, macrophages are mainly divided into clas- models, although there is some overlap between in vivo M1
sically/inflammatory activated macrophages (M1 macro- (LPS+) and in vitro classical activation and in vivo M2 (LPS-
phages) and alternatively/wound healing-activated ) and in vitro alternatively activated macrophages, more genes
macrophages (M2 macrophages), which are the two termi- are regulated in opposite or unrelated ways. For example, che-
nal states of macrophage polarization depending on their mokine CCL2, hematopoietic cytokine Csf2 (GM-CSF), IL-15,
polarization status and function. Later, some scholars IL-23a, and IFNβ1 positively correlate with M1 polarization
referred to the basic principle of the three primary colors in vivo but do not increase in vitro classically activated macro-
in the color wheel and divided macrophages into classically phages [65]. Those can explain that in vitro classical and alter-
activated macrophages, wound healing macrophages, regu- native macrophage activation does not match M1/M2
lated macrophages, and hybrid macrophage groups with polarization in vivo, suggesting that we should pay attention
the characteristics of the above two macrophages at the same to the nonnegligible differences in macrophages in different
time [39]. But in the new nomenclature proposed by Murray environments (in vivo/in vitro).
et al., it is also proposed to avoid the term “regulatory mac-
rophage” and recommend describing the stimulation scene 3.5. Macrophage Polarization and Noncoding RNAs. In addi-
and stimulator to define the macrophage activation state tion to IFN-γ, LPS, IL-4, TNF-α, GM-CSF-1, and M-CSF,
[40]. Therefore, although the “M1-M2 paradigm” is a more noncoding RNAs can also regulate macrophage polarization.
 4

Table 1: Phenotypes, stimulants, biomarkers, secretions, and functions of macrophages.

Macrophage phenotype Stimulants Biomarkers Secretions Functions Ref.

Promote Th1 immune response, promote
CD86, CD40,
IFN-γ, LPS, TNF-α, IL-1α, IL-12, IL-23, IL-1β, inflammatory response, fight pathogens, and
M1 (classically activated macrophages) CD38, NF-κB, [7, 8, 42–45]
TNF-α, GM-CSF IL-6, ROS, and RNS inhibit the occurrence and development of
STAT1
tumors
Promote tissue repair and remodeling,
CD206, IL-1R,
IL-4, IL-13, TGF-β, IL-10, insulin-like growth promote fibrosis, and promote type II
M2a (wound healing macrophages) CCL17, Fizz1, [45, 53–56]
M-CSF factor (IGF), and fibronectin immune response by enhancing polyamines,
STAT6
collagen synthesis
Immune IL-10, CCL1, Proinflamatory cytokines (IL-1β,
Involve in proinflammatory and anti-
complex, TLR LIGHT, CD86, IL-6, and TNF-α), anti-
M2b (regulatory macrophages) inflammatory responses, [45, 54–58]
agonist, IL-1R SPHK1, TNF-α, IL- inflammatory cytokine (IL-10 and
immunomodulation, and Th2 activation
agonist 6, ERK, AP-1 low levels of IL-12)
CD163, Mer
Immune tolerance and tissue repair,
Glucocorticoids, receptor tyrosine
M2c (acquired inactivated macrophages) IL-10, TGF-β suppress inflammation, promote [45, 55, 56, 58, 59]
TGF-β, IL-10 kinase (MerTK),
phagocytosis and cholesterol efflux
STAT3
Vascular
TLR, adenosine Proteolytic enzymes (MMP-2),
endothelial growth Beneficial for angiogenesis and tumor
M2d (tumor-associated macrophages A2A receptor growth factors (VEGF), and anti- [45, 55, 56, 60–64]
factor A (VEGF-A), metastasis
γ, IL-6 inflammatory mediators (TGF-β)
HIF-1α
Mediators of Inflammation
Mediators of Inflammation 5

Table 2: MicroRNAs involved in regulating macrophage polarization.

MicroRNA Organism Cell Target Function Ref.

SOCS1, IL-13Rα1, Activates STAT1 and inhibits STAT6,
miR-155 Human Monocytes [67]
C/EBP-β thereby promoting macrophage polarization
Peripheral blood TRAF6, IRAK1, Limits NF-κB and IRF3 and inhibits
miR-146a Human [68]
mononuclear cells IRAK2, IRF3 M1 macrophage polarization
IRF5 is inhibited by the PI3K pathway,
miR-let-7a Human Macrophages HMGA2 [69]
thereby inhibiting M1 macrophage polarization
AMP activates protein Promotes M2 macrophage polarization,
miR-33 Mouse Monocytes [70]
kinases (AMPK) elevates Treg cells
Promotes M2 macrophage polarization,
miR-223 Mouse Macrophages Pknox1, Sp3 [71]
inhibits NLPR3 inflammasome
Promotes M2 macrophage polarization,
miR-21 Human Macrophages PTEN, PDCD4 decreases NF-κB signaling, and [72]
increases IL-10 production
miR-125a Human Macrophages FIH1, IRF4 Promotes M1 macrophage polarization [73]
Mesenchymal Promotes M2 macrophage polarization by
miR-100-5p Human Unknown [74]
stem cells regulating the PI3K-AKT pathway
Reduces macrophage downstream
miR-654 Human Macrophages MIF proinflammatory cytokines by inhibiting [75]
phosphorylation of ERK and AKT
Tubular Activates the STAT3 signaling pathway to
miR-382 Mouse SIRP-α [76]
epithelial cells promote M2 macrophage polarization
Inhibits the JAK3/STAT3 pathway to
miR-221-3p Human Macrophages JAK3 [77]
promote M1 macrophage polarization
miR-467f Mouse Macrophages Map3k8, Mk2 Inhibits M1 macrophage polarization [78]
Inhibits NF-κB activation and negatively
miR-93 Rat Macrophages IRAK4 [79]
regulates M1 macrophage polarization

Noncoding RNA refers to RNA that participates in the tran- miR-200c, stimulates M2 macrophage polarization, and pro-
scription process of genes but does not translate proteins, motes renal fibrosis [89]. Nevertheless, it is still unclear in
mainly including microRNA (miRNA), long noncoding the mechanism of circular RNA-mediated macrophage
RNA (lncRNA), and circular RNA (circRNA) [66]. Noncod- polarization and needs to be further explored. Currently, it
ing RNA can affect the polarization balance of macrophages has reached some consensus that noncoding RNAs play an
through different mechanisms of action. essential role in macrophage polarization, and these noncod-
miRNAs are evolutionarily highly conserved noncoding ing RNAs can serve as effective biomarkers for disease diag-
RNAs with a length of about 22 nucleotides involved in nosis and therapeutic targets.
immune responses and tumor growth regulation. Currently,
a large number of miRNAs have been identified, of which 3.5.1. Noncoding RNAs and Systemic Lupus Erythematosus.
some can regulate macrophage polarization, such as miR- An in vitro study confirmed that lncRNA-GAS5 expression
156a, miR-33, miR-let-7a, miR-223, miR-155, miR-21, is downregulated in SLE [90]; meanwhile, knockdown of
miR-125a, miR-19b-3p, miR-100-5p, miR-654, and miR- lncRNA-RN7SK and lncRNA-GAS5 can downregulate the
221-3p [67–79], as shown in Table 2. levels of M2 markers (CD163, CD206, or Dectin) and upreg-
lncRNAs are non-protein-coding RNAs with a length of ulate the levels of M1 markers (MHC II or CD23), confirm-
more than 200 nucleotides, which are involved in cell differ- ing that both lncRNA-RN7SK and lncRNA-GAS5 can
entiation and proliferation, cycle regulation, tumor develop- promote M2 macrophage polarization and therefore exert
ment, and other pathophysiological processes. Macrophage a mitigating effect on SLE [80, 90]. Nevertheless, how non-
polarization is also affected by some lncRNAs, such as coding RNA regulates macrophage polarization to affect
ANCR, Mirt2, HITT, GAS5, and RN7S [80–86], as shown the pathogenesis of SLE is still unclear.
in Table 3.
In addition, circRNAs are a new hotspot in the field of 3.5.2. Noncoding RNAs and Lupus Nephritis. It is found that
RNA research and are a special noncoding RNA. They have lncRNA NEAT1 is up-regulated in SLE patients and can
also been confirmed in the latest study to promote macro- enhance the expression of cytokines or chemokines such as
phage polarization to M2 and thus participate in the regula- IL-6, CCL2, and CXCL10 by phosphorylating JNK and
tion of disease. circSAFB2 mediates M2 macrophage ERK. These cytokines can attract Th1 cells and participate
polarization through the miR-620/JAK1/STAT3 axis [87, in the pathogenesis of LN [91]. Meanwhile, it is also con-
88], while circACTR2 activates YAP signaling by targeting firmed that lncRNA NEAT1 participates in TLR-mediated
6 Mediators of Inflammation

Table 3: lncRNAs involved in regulating macrophage polarization.

lncRNA Organism Cell Target Function Ref.

lncRNA GAS5 Human Macrophages CCL1 Promotes M2 macrophage polarization [80]
Promotes M2 macrophage polarization,
lncRNA RN7SK Human Macrophages P-TEFb negatively regulates antigen uptake/processing [80]
and bacterial phagocytosis
Reduces the level of IL-6 and IL-1β in cells,
lncRNA ANCR Mouse Macrophages FOXO1 [81]
inhibits M1 macrophage polarization
Inhibits the activation of NF-κB and
lncRNA Mirt2 Mouse Macrophages TRAF6 MAPK pathways and inhibits [82]
M1 macrophage polarization
Promotes M2 macrophage polarization,
lncRNA FAO Mouse Macrophages HADHB subunit [83]
inhibits proinflammatory cytokines
Bone marrow-derived Inhibits the STAT6 pathway,
lncRNA GBP9 Mouse SOCS3 [84]
macrophages promotes M1 macrophage polarization
Induces the polarization of
lncRNA GAS5 Mouse Microglia TRF2 [85]
macrophages to M2
Activates the JAK-STAT and PI3K/AKT
Interleukin-28
lncRNA260 Rat Macrophages signaling pathways to promote [86]
receptor α
M2 macrophage polarization

inflammatory response in monocytes through the MAPK 3.5.5. Noncoding RNAs and Autoimmune Uveitis. In addi-
pathway [92]. MicroRNA-382 can activate the STAT3 sig- tion, microRNAs are closely associated with autoimmune
naling pathway by downregulating signal regulatory protein uveitis. miRNAs can participate in the inflammatory or
α (SIRP-α) to promote M2-type macrophages, and sustained inflammatory mitigation process of uveitis by acting on sig-
M2 macrophage infiltration promotes renal fibrosis. How- naling molecules of the NF-κB pathway in macrophage
ever, microRNA-382 knockout or M2 macrophage depletion polarization [94]. The toll-like receptor (TLR4) in the NF-
can inhibit the expression of α-SMA, fibronectin, and colla- κB pathway can recruit MyD88 and IRAK after LPS stimula-
gen I and exhibit a certain mitigating effect on kidney fibers tion, and IRAK phosphorylation activates NF-κB after inter-
[76], indicating that miR-382 may become a promising ther- acting with TRAF6 to promote M1 production. In an animal
apeutic target in the future. model of endotoxin-induced uveitis (EIU), miR-93 was
found to bind to IRAK4 in the NF-κB pathway, thereby inhi-
3.5.3. Noncoding RNAs and Rheumatoid Arthritis. In the biting NF-κB activation and thus negatively regulating the
synovial chamber of RA patients, the expression of miR- generation of M1-type macrophage-related proinflamma-
221-3p is abnormally increased, and M2 macrophages are tory cytokines [79]. miR-30b-5p is downregulated in the
transferred to proinflammatory M1 through the JAK3/ spleen, lymph nodes, and eye tissues of rats with autoim-
STAT3 pathway, promoting the development of joint mune uveitis, and both in vitro and in vitro experiments
inflammation [77]. In an in vitro cell experiment in RA have confirmed that supplementation with miR-30b-5p can
patients, the drug tocilizumab has a certain alleviating effect reduce the level of IL-10 and TLR4-positive cells, thereby
on inflammation, mainly by inducing lncRNA MIR31HG, having a certain inhibitory effect on uveitis [95]. Meanwhile,
reducing miR-214, inhibiting the macrophage AKT path- miR-155 has been shown to promote M1 macrophage polar-
way, and decreasing proinflammatory M1 macrophage fre- ization and thus exert proinflammatory effects, showing
quency, thereby exhibiting a certain protective effect on remission to EAU after reducing miR-155 expression levels
chondrocytes [93]. [67, 96]. However, how miR-155 regulates the polarization
of macrophages by regulating the expression of target genes
3.5.4. Noncoding RNAs and Multiple Sclerosis. lncRNA and then affects the pathogenesis of uveitis needs to be fur-
GAS5 inhibits M2 polarization and intensifies demyelinating ther investigated.
by inhibiting transcription of TRF2, a critical factor in M2
macrophage polarization, and interfering with microglial 3.5.6. Noncoding RNAs and Sjogren’s Syndrome. Interest-
GAS5 in vitro experiments can attenuate the progression ingly, studies have shown that different lncRNAs and miR-
of experimental autoimmune encephalomyelitis (EAE) NAs are differentially expressed in primary SS and
[85]. At the same time, the latest research found that miR- participate in the pathogenic process of the disease [97,
467f and miR-466q can inhibit the expression of Map3k8 98]. A rabbit model of autoimmune dacryoadenitis found
and MK2 and attenuate the proinflammatory phenotype of that small extracellular vesicles derived from human umbil-
microglia through the p38 MAPK signaling pathway, thus ical cord mesenchymal stem cells promote M2 macrophage
having a good alleviating effect on the neuroinflammation polarization and induce Tregs by miR-100-5p, thereby alle-
of MS [78]. viating autoimmune dacryoadenitis [99].
Mediators of Inflammation 7

Collectively, a deep understanding of the mechanism of forms of the disease [109]. Organ-threatening or life-
noncoding RNAs regulating macrophage polarization under threatening SLE usually includes initial high-intensity
different conditions can more effectively help us manipulate immunosuppressive therapy to control disease activity,
the expression and silence these noncoding RNAs through followed by long-term low-intensity therapy to consolidate
drug targeting to control the direction of macrophage polar- the response and prevent recurrence [110].
ization, opening up a new horizon for the treatment of The pathogenesis of SLE is not only related to the abnor-
inflammatory diseases. mality of B cells and T cells but also related to inflammation-
promoting M1 and immunosuppressive M2. It is confirmed
3.6. Macrophage Polarization and Autoimmune Diseases that biological factors that promote the polarization of M1
macrophages will exacerbate the inflammation of SLE, and
3.6.1. Profiling of Autoimmune Disease. Autoimmune dis- M2 is also involved in the pathogenesis of SLE. Human cyto-
eases are clinical diseases caused by the destruction of auto- megalovirus (HCMV) has been shown to be one of the
immune tolerance or abnormal regulation of autoimmune major factors that can trigger SLE. In a clinical study involv-
cells, the continuous immune response of the immune sys- ing SLE patients, HCMV infection-associated human cyto-
tem to autoantigens, and the damage or dysfunction of megalovirus protein (US31) was elevated in SLE patients
self-organizing cells induced by some genetic and environ- and promoted NF-κB2 activation, leading to M1 macro-
mental factors [100]. phage polarization and further deterioration of SLE [111].
Notably, age and gender are the related factors that In addition, a recent in vitro experiment found that toll-
induce autoimmune diseases. Most autoimmune diseases like receptor 7 and toll-like receptor 9 (TLR7 and TLR9)
can occur at any age; however, some autoimmune disorders agonists can activate peritoneal macrophages to secrete
mainly occur in childhood and adolescence (such as type I higher levels of proinflammatory factors, thereby aggravat-
diabetes), middle adulthood (such as myasthenia gravis ing disease progression in mice [112]. Interestingly, SLE
and multiple sclerosis), or the elderly (such as rheumatoid activity is also related to macrophage polarization, and active
arthritis and primary systemic vasculitis) [101]. The inci- SLE is more inclined to the expression of proinflammatory
dence rate of autoimmune diseases accounts for approxi- M1 macrophages [113]. In the subtype of M2 macrophages,
mately 5-10% of the total population. For most we already know that M2a has the function of promoting tis-
autoimmune diseases, there are significant gender differ- sue repair and fibrosis. M2b participates in immune and
ences in prevalence, and women are usually affected more inflammatory responses, and M2c is involved in inactiva-
frequently than men. For example, women are about nine tion, remodeling, and anti-inflammatory processes [114].
times more likely to develop systemic lupus erythematosus Each subtype plays an individual role in SLE. In the later
(SLE) than men, dramatically impacting the quality of life stages of SLE, fibrosis is a common clinical manifestation
of female patients [102, 103]. This sex difference may con- attributed to the function of macrophages, especially end-
tribute to estrogen. After estrogen binds to immune cell stage renal fibrosis, which is closely related to the CD206
receptors, it can participate in the regulation of transcription subset of M2 macrophages, but whether it is related to
factors, such as activating protein 1 (AP-1) and NF-κB as a M2a macrophages has not been reported [115, 116]. M2b
cofactor, possessing a certain pathogenic effect on SLE and is considered to be related to the inflammatory pathology
multiple sclerosis (MS) [104]. Currently, the main goal of of SLE, and the IL-10 and IFN-γ of M2b expressions can
treating autoimmune diseases is to alleviate inflammation, be detected in serum samples of SLE patients, which is asso-
relieve symptoms, attenuate organ damage, and minimize ciated with the deposition of immune complexes in SLE as a
the possibility of recurrence [105], prolonging patients’ sur- good inducer of M2b activation [117]. A recent animal
vival time and optimizing the individual quality of life. model of SLE mice showed that blocking the Notch1 signal-
ing pathway can hinder the polarization of M2b macro-
3.6.2. Macrophage Polarization and Systemic Lupus phages and improve lupus symptoms in SLE mice [118].
Erythematosus. SLE is an autoimmune connective tissue dis- Therefore, selective inhibition of M2b activity can reduce
ease that often involves multiple systems, with a wide range its proinflammatory effect and tissue damage. There are still
of clinical manifestations. It usually occurs in young women many unknowns about the regulation of subtypes under M2
aged between 20 and 40. At present, the potential incidence polarization, and we need to further fill the gap. Similarly,
rate and mortality are significant, and the pathogenesis and defective M2-like macrophages exacerbate the development
etiology are still unclear [106, 107]. Clinically, the diagnosis of SLE by uncontrollably secreting cytokines and promoting
of SLE is mainly based on the combination of typical clinical abnormal deposition of immune complexes, such as M2-like
manifestations and serological positivity, and characteristic macrophages lacking heme oxygenase-1 expression found in
clinical manifestations include cutaneous lupus erythemato- lupus nephritis, a complication of SLE [42].
sus, alopecia, joint pain caused by musculoskeletal involve- A large number of studies have found that promoting
ment, proteinuria caused by kidney involvement, and the activation of M2 macrophages and returning the M1/
mental abnormalities caused by central nervous system M2 macrophage ratio to normal level play a specific role in
involvement (seizures, psychosis, and coma) [108]. Cur- alleviating SLE. JAK/STAT signaling pathway is an impor-
rently, there are four main types of treatment for SLE: non- tant pathway that regulates the polarization direction of
steroidal anti-inflammatory drugs, antimalarial drugs, macrophages. JAK (Janus kinase) kinase family plays a cru-
glucocorticoids, and immunosuppressive drugs for heavier cial role in the immune system and is a series of pathological
8 Mediators of Inflammation

therapeutic targets, including autoimmune diseases, Fc receptors and certain TLRs, decrease immune complex
COVID-19-related cytokine storms, and blood cancer [119, (IC) deposition, reduce autoantibody IgG levels, and down-
120]. In an in vitro experiment, it was found that peripheral regulate inflammatory mediators (TNF, IL-1β, and IL-60)
blood-derived mesenchymal stem cells could secret IL-10 to [130]. These two viewpoints are consistent and show that
induce the upregulation of JAK1/STAT3 signaling in macro- BTK inhibitors can promote M2 macrophage polarization,
phages, thereby promoting an increase in the expression of reduce the production of inflammatory factors, improve
M2-type macrophages and M2-related cytokines [121]. It is the renal microenvironment, and play an excellent protec-
known that most TLR agonists activate M1 macrophage tive and therapeutic role in the damaged kidney in LN.
polarization; in contrast, the toll-like receptor 2/1 agonist Although BTK inhibitor as a drug has successfully treated
PAM3 can induce human monocytes to differentiate into rheumatoid arthritis and multiple sclerosis in the clinic, fur-
M2-like macrophages in vitro and in vivo. The underlying ther efforts are still needed in the clinical application in
mechanism involved in this process is due to PAM3 promot- treating SLE and Sjogren’s syndrome [131].
ing monocytes differentiating into immunosuppressive mac- The NLRP3 inflammasome is a cytosolic protein com-
rophages by regulating the p38 MAPK and PTGS2 pathways posed of the innate immune receptor protein NLRP3,
in monocytes [122, 123]. In addition, this study also found adapter protein ASC, and inflammatory protease caspase-1,
that type I interferon can participate in the pathogenesis of playing a vital role in regulating autoimmune diseases
SLE through the JAK/STAT pathway and is positively corre- [132]. The NLRP3 inflammasome is closely related to LN.
lated with the development of SLE. Moreover, serine/threo- Activation of NLRP3 inflammatory corpuscles can increase
nine kinase AKT2 can act with IRF3 to weaken IRF3 the release of proinflammatory factors, stimulate macro-
nuclear translocation, thereby reducing the production of phages to polarize into M1, and aggravate the damage of
type I interferon. Thus, AKT2 may have a particular targeted LN. An in vitro human monocyte study found that olea-
therapeutic effect on SLE [124]. mide, an endogenous fatty acid primary amide, can activate
NLRP3 inflammasome, increasing cytokine IL-1β and mac-
3.6.3. Macrophage Polarization and Lupus Nephritis. Lupus rophage polarization to proinflammatory M1 metastasis
nephritis (LN) is a common SLE complication that can lead [133]. Therefore, lentivirus-mediated Fcγ receptor I (Fcγ
to severe tissue damage and organ failure. The pathogenesis RI) by inhibiting nuclear factors-κB (NF-κB) could reduce
of LN is related to immune complex deposition, macrophage the activation of NLRP3 inflammasome, inhibit renal
activation, and excessive release of proinflammatory cyto- inflammation, and reduce the toxic effect of LN [134]. An
kines. Activation of the immune complex of Fcγ receptors experimental study revealed that miR-654 treatment effec-
on Fc receptor-carrying cells (monocytes and macrophages) tively improves LN in rats by inhibiting macrophage migra-
can lead to the release of inflammatory cytokines, thereby tion inhibitory factor (MIF), selectively inhibiting ERK and
causing kidney inflammation [125]. Macrophages are the AKT phosphorylation, and reducing the production of
primary infiltrating cells in the kidney of LN patients and downstream inflammatory cytokines [75]. Interestingly,
participate in the injury and repair of the kidney. Immature stimulation of human M2-like macrophages with type I
macrophages can be detected in the urine of patients with interferons can lead to decreased HO-1 expression and ele-
LN, and the frequency of those macrophages is associated vated Bach1 and IL-6 expression, suggesting that dysregu-
with the disease progression [126]. lated M2-like macrophages play a proinflammatory role in
Evidence has shown that M1 macrophages from the LN. Bach1 may be a potential therapeutic target that could
injured kidney have proinflammatory effects and clear apo- restore the anti-inflammatory property of M2 macro-
ptotic and injured cells. M2-type macrophages play a role phages [135].
in inhibiting inflammation and promoting tissue repair,
while M2a-like macrophages are involved in fibrosis repair 3.6.4. Macrophage Polarization and Rheumatoid Arthritis.
and progression [127], and M2c can exert anti- Rheumatoid arthritis (RA), a commonly autoimmune dis-
inflammatory and profibrotic effects [128]. Thus, changing ease in clinical practice, is a chronic synovial proliferative
the direction of macrophage polarization can worsen or inflammation. Inflammatory changes are mainly seen in
improve the development and prognosis of LN. In most the synovial tissue of joints, cartilage, and bones, rarely in
cases, alleviation of LN is mainly achieved by increasing extra-articular areas such as skin and blood vessels. The
the frequency of M2 macrophages and enhancing the anti- prevalence rate of RA is between 0.4% and 1.3% of the pop-
inflammatory properties. For example, using the pristane- ulation, and the prevalence rate of women is 2-3 times
induced mouse animal model, it was found that total gluco- higher than that of men [136, 137]. To date, the etiology is
sides of peony (TGP) could efficiently increase the frequency still unclear. It is reported that the risk factors of RA include
of M2 macrophages through the IL-4-mediated STAT6 sig- smoking, improper diet, exposure to ultraviolet rays, sex
nal transduction pathway and play a therapeutic role in LN hormones, drugs, and periodontitis [138]. The main clinical
through its anti-inflammatory effect [129]. manifestations are low fever, weight loss, joint injury, and
The lack of Bruton’s tyrosine kinase (BTK) could dysfunction. When patients with RA get up early, they usu-
enhance STAT6 phosphorylation through the STAT signal- ally have inflexible joint activities, including morning stiff-
ing pathway, resulting in decreased M1 polarization and ness and multiple joint symmetry involvement, often
increased M2 polarization. In addition, the BTK inhibitor leaving joint deformities [139]. The diagnostic basis of RA
BI-BTK-1 can prevent macrophage activation by inhibiting includes patients’ clinical symptoms, risk factor assessment,
Mediators of Inflammation 9

family history, and laboratory tests such as detecting bio- switching and migration response. Sirt6 inhibits NF-κB-
markers (e.g., erythrocyte sedimentation rate in serum, C- mediated inflammatory response by interacting with the
reactive protein, and RA-specific autoantibodies) [138, RelA subunit of NF-κB, so when Sirt6 is deficient, it will
140]. Clinically, the treatment of RA includes drug treat- promote NF-κB activation and endogenous production of
ment, immune purification, surgical treatment, and patients’ IL-6, thereby enhancing macrophage infiltration and M1
self-strengthening functional exercise [141, 142]. macrophage activation in the joint, aggravating inflamma-
Macrophages can polarize to M1 or M2 when stimulated tion and leading to the development and deterioration of
by different environmental factors, and the dynamic polari- RA [153, 154]. Macrophage polarization plays an essential
zation process from M1 to M2 includes the presence of role in the progression of RA. Therefore, drug regulation
intermediate polarity stages. M1/M2 polarization imbalance of macrophage repolarization may be an effective method
contributes to acute or chronic RA [15, 143]. In recent years, for targeted therapy of RA. Interestingly, using a RA
studies have found that classically activated M1 macro- mouse model, plasmid DNA encoding the anti-
phages secrete high levels of proinflammatory cytokines inflammatory cytokine interleukin-10 (IL-10) pDNA and
and chemokines and induce early inflammatory lesions in the chemotherapeutic drug betamethasone sodium phos-
RA, and the symptoms and signs of rheumatoid arthritis phate (BSP) can be packaged into M2 exosomes to pro-
(RA) are exacerbated with the increase of proinflammatory mote M1-to-M2 repolarization [155].
cytokines [16]. Activation of the NLRP3 inflammasome via
the NF-κB pathway and gasdermin family-driven phosphor- 3.6.5. Macrophage Polarization and Multiple Sclerosis. Multi-
ylation is all related to the inflammatory process of RA ple sclerosis (MS) is a progressive demyelinating disease of
[144]. In the remission of RA, the expression of the M2 mac- the central nervous system (CNS). It is also a tremendously
rophage (MerTK+CD206+) significantly increased, and the challenging autoimmune disease in the clinic. At present,
secretion of anti-inflammatory cytokines by M2 macro- the etiology of MS is still unclear. Given multiple factors,
phages alleviates the symptoms and signs of RA [145]. MS is related to genetic and environmental factors, such as
MERTK macrophages can release lysin D1 and induce the virus infection, smoking, and decreased vitamin D levels
expression of collagen genes such as COL1A to promote [156–158]. In accordance with the clinical course, it is
fibroblast repair phenotype, while the binding of MERTK mainly divided into four types: relapsing-remitting (RR),
to exposed phosphatidylserine (PS) on apoptotic cells fur- primary progressive (PP), secondary progressive (SP), and
ther exerts phagocytosis [146, 147]. M2 macrophages, an progressive-relapsing (PR), of which RRMS is the most com-
anti-inflammatory/prorepair process, shift the disease from mon MS [159]. MS lesions are diffuse and multiple, the clin-
active to remission. Thus, in situ guided macrophage repro- ical manifestations of patients are complex, and different
gramming provides valuable clues to alter the activity and symptoms and signs occur due to the difference in lesion
severity of RA. In a mouse arthritis study, the use of M2 sites, including neuritis, limb paralysis, retrobulbar optic
macrophage-derived extracellular vesicles (rich in proteins neuritis, mental symptoms, deafness, and vertigo [160].
known to be involved in M2 production as well as macro- Clinically, the diagnosis of MS is based on McDonald’s diag-
phage reprogramming factors) can drive synovial macro- nostic criteria, which mainly link the patient’s clinical man-
phage polarization from the M1 type to the M2 phenotype, ifestations, magnetic resonance imaging (MRI), and
thereby reducing joint damage and inflammatory responses brainstem auditory evoked potential and cerebrospinal fluid
in mice [148]. In addition, we can also alleviate disease (CSF) examination for diagnosis [161].
severity by directly reducing M1 and even reducing related MS is an immune-mediated chronic inflammatory dis-
chronic pain. For example, glaucocalyxin B (Gla B) can min- ease, and the homeostasis of M1/M2 macrophages plays a
imize M1 polarization in synovial macrophages by inhibiting prominent role in developing MS. In multiple sclerosis, M1
P65 expression in the NF-κB pathway [149]. Wilforlide A, and M2 macrophages can coexist and play a dual role, play-
an active compound in Tripterygium wilfordii Hook F, can ing a neuroprotective role by producing inflammatory medi-
participate in macrophage polarization through the TLR4/ ators that cause nerve tissue damage and can promote
NF-κB pathway and inhibit LPS/IFN-γ-induced upregula- growth support repair. Vogel et al. found that most foam
tion of TLR4, which in turn inhibits NF-κB activation and macrophages in active MS lesions can express both M1
reduces M1 polarization [150]. As we all know, TNF can and M2 markers, confirming the existence of an intermedi-
serve as a driver of RA, so anti-TNF drugs can promote ate state of macrophage activation [162]. Macrophages can
M2 polarization by targeting the IL-10/STAT3 pathway form microglia within the CNS and are mainly involved in
[151]. Thus, these drugs play an excellent role in alleviating inflammation and demyelination in MS. In laboratory
RA. In addition, recent studies have also shown that moxi- research, its animal model is experimental autoimmune
bustion has a particular therapeutic effect on RA. Moxibus- encephalomyelitis (EAE). After activation, macrophages will
tion is a form of traditional Chinese medicine that mainly release a variety of cytokines to promote the development of
promotes M2 polarization through activating JAK1, JAK3, the disease, and M1 macrophages have a higher proinflam-
and STAT6 in the IL-4/STAT6 signaling pathway, thus matory spectrum in EAE [163]. It has been found that differ-
reducing inflammatory cell infiltration and vasodilation, ent macrophage polarization types are involved in different
and helps alleviate the effects of RA [152]. Moreover, stages of MS development. In the early or acute phase of
researchers also confirmed that sirtuin 6 (Sirt6) in bone mar- MS, the polarization of microglia/macrophages to M1 pro-
row cells plays a crucial role in macrophage phenotypic motes inflammatory damage to the nervous system. For
10 Mediators of Inflammation

example, circ_0000518 has been found to be elevated in MS. most common animal model of GBS in scientific research
As the circ_0000518 RNA-binding protein, FUS can bind is experimental autoimmune neuritis (EAN). The EAN ani-
circ_0000518 and promote M1 macrophage polarization mal model is established via immunizing Lewis rats with
through the CaMKKβ/AMPK pathway, thereby aggravating myelin or myelin P2 and P0 from Freund’s adjuvants to
the continued progression and deterioration of MS [164]. develop transient paralysis [174]. The pathological manifes-
In the late stage or recovery period of MS, microglia/ tations of neuroedema, perivenous lymphocyte infiltration,
macrophages polarize to M2, promote tissue repair, and and macrophage-mediated demyelinating are the same as
reduce the severity of MS. Therefore, the treatment of MS GBS.
mainly regulates macrophage polarization and cytokine M1 and M2 macrophages can guide T cell polarization
levels and cytokine levels to improve the immune microen- in different ways. At different stages of GBS, macrophages
vironment. In recent years, dimethyl fumarate (DMF) has play either a proinflammatory or anti-inflammatory role.
exhibited an excellent therapeutic effect on recurrent remit- In the early stage of GBS, M1 macrophages promote cyto-
ting MS. DMF can effectively improve the clinical score of toxicity and Th1 cytokine production, leading to inflamma-
MS patients, activate the antioxidant product of Nrf2, and tory damage of myelin sheath and disease development
reduce the tissue damage caused by ROS in MS and EAE [175]; in the late stage of GBS, M2 macrophages promote
animal models [165]. In addition, in an in vitro rat model, Th2 immune response and the secretion of anti-
DMF can efficiently reduce proinflammatory mediators such inflammatory cytokines and participate in the recovery of
as iNOS, TNF-α, IL-1β, and IL-6 synthesized by reducing disease and the repair of the myelin sheath and axons
ERK phosphorylation to promote M2-like macrophages [176]. M1 macrophage-derived exosomes can exacerbate
[165, 166]. Moreover, the p38MAPK/SGK1 signaling path- EAN by enhancing the Th1 and Th17 responses, while M2
way can promote M2 macrophage polarization and alleviate macrophage-derived exosomes reduce disease severity [177].
the severity of EAE in the MS model [167]. The Notch signaling pathway is an important pathway
At present, biogenic amines’ role in treating MS has for macrophage polarization. The Notch receptor family
powerfully attracted attention. Biogenic amines mainly consists of 4 members (Notch1-4), the ligand family consists
include serotonin (5-HT), dopamine, and norepinephrine. of 5 members (Delta1, Delta3, Delta4, Jagged1, and Jagged2),
Among them, 5-HT may regulate M2 macrophage polariza- and NICD and RBP-J as the downstream molecules of the
tion [168]. Regarding dopamine, it can directly recruit Notch signaling pathway are also actively involved in the
TRAF6 and its negative regulator ARRB2 as well as down- regulation of M1 macrophage polarization [178]. Oridonin
stream signaling proteins such as TAK1, IKK, and PP2A (a herbal extract compound) may downregulate the expres-
through its receptor DRD5 on macrophages to form a multi- sion of Notch1, Jagged-2, and downstream molecules by
protein complex, thereby inhibiting the activation of blocking the Notch pathway, promoting the transfer of M1
TRAF6-mediated NF-κB and the expression of proinflam- to M2, leading to the reduction of proinflammatory cyto-
matory genes, which may exert a particular inhibitory effect kines, and significantly improving the progression of EAN
on macrophage polarization to M1 [169]. Meanwhile, dopa- [179]. The NF-κB signaling is also an effective target for
mine inhibits nuclear translocation of NF-κB p65 by form- the treatment of EAN. Thus, reducing the polarization of
ing dopamine quinones in microglia, thereby attenuating M1 macrophages and promoting the polarization of M2 by
proinflammatory cytokine expression, a process that may inhibiting p65 phosphorylation in the NF-κB pathway can
be associated with reduced polarization of M1 macrophages alleviate EAN [180].
[170]. These findings indicate that some biogenic amines can
regulate macrophage polarization in MS, and researchers 3.6.7. Macrophage Polarization and Autoimmune Uveitis.
need to pay more attention to the molecular mechanism of Uveitis is an inflammatory disease of the iris, ciliary body,
macrophage polarization in MS in the future. and choroid tissue in the eye. Clinically, approximately
In addition, studies have also found that mitochondrial 35% of uveitis patients have a severe visual impairment or
fission inhibitor (MDivi-1) can improve the inflammation even blindness. The etiology of uveitis is complex and can
of EAE mice, mainly by inhibiting TLR2/4 and GSK3β- be divided into infectious or noninfectious uveitis. Many
mediated NF-κB activation to promote M2 polariza- studies have confirmed that noninfectious uveitis is mainly
tion [171]. related to autoimmunity, that is, the deposition of antigen-
antibody complexes in the capillary-rich uvea. It is reported
3.6.6. Macrophage Polarization and Guillain-Barre that uveitis primarily occurs in young people. Currently, the
Syndrome. Guillain-Barre syndrome (GBS) is a peripheral main treatment methods include the local or systemic appli-
nerve disease characterized by demyelinating lesions of cation of glucocorticoids and ciliary muscle paralysis [181].
peripheral nerves, nerve roots, and infiltration of small vas- Experimental autoimmune uveitis (EAU) is an ideal ani-
cular inflammatory cells [172]. It is a relatively rare autoim- mal model of human autoimmune uveitis. EAU model
mune disease. Patients with GBS often have sensory and induction is the immunization of susceptible rodents using
motor disorders, such as muscle weakness, limb paralysis, proteins or peptides extracted from the retina, iris, or ciliary
and limb numbness. To date, the etiology of GBS has not body. This process is combined with complete Freund’s
been fully addressed, but in most cases, it is easy to develop adjuvant and tuberculin. Mice are more accessible to trans-
after bacterial or viral infection, which is more common in gene and propagation than other animals, and the eye struc-
men, and the incidence rate increases with age [173]. The ture of mice is similar to that of human beings, so most of
Mediators of Inflammation 11

the research in recent years has used EAU mouse animal are diverse and can involve the whole-body system and spe-
models [174, 182]. Macrophages participate in the whole cific target organs [193]. It is mainly due to the abnormal
process of EAU and play different roles in different stages function of lacrimal glands and salivary glands, leading to
of the development of EAU [183]. It is well known that when dry skin and mucosa. Currently, the clinical diagnosis largely
macrophage M1/M2 polarization is unbalanced, it will affect depends on patients’ physical signs, pathological biopsy,
the differentiation of Th cells, leading to the imbalanced imaging examination, and detection of autoantibodies.
Th1/Th2 and Th17/Treg ratios. Th1 and Th17 reactions The etiology of SS is still unclear, but sustained B-cell
can aggravate inflammation-related pathogenicity, whereas activation and proliferation of Th1 and Th17 cells contribute
Th2 and regulatory T (Treg) reactions can alleviate the pro- to disease progression [194]. IFN-induced gene overexpres-
cess of EAU [184]. The Notch signaling pathway plays a key sion has been found in patients with SS, including
role in the pathogenesis of EAU. It has been confirmed that interferon-induced protein 44 (IFI44) and transporter 2
the expression of Notch1, DLL4, IL-10, IL-17, RORγt, and ATP-binding cassette (TAP2) [195, 196]. Moreover, there
Foxp3 is elevated in the pathogenesis of EAU, and increased is an interaction between IFN and B lymphocyte activation,
polarization of M1 macrophages and an imbalance in the and B cells can induce the production of IFN, which in turn
ratio of Th17/Treg occur [185]. Similarly, using an EAU facilitates the production of autoantibodies [79, 195]. There-
rat model, it is found that Longdan Xiegan decoction fore, the pathogenesis of SS in the innate immune system is
(LXD), a traditional Chinese medicine compound, can effec- closely related to the presence of type I interferon [197]. In
tively decrease the expression of Notch 1 and Delta4, inhibit adaptive immunity, B cells and T cells are activated by type
the activation of the Notch pathway, and reduce the expres- I and II interferons. Adaptive immunity involves B cell acti-
sion of IL-17 to alleviate the ocular inflammatory reaction vation to produce antibody and T cell polarization, in which
and effectively improve the intraocular immune microenvi- Th1 and Th17 proportions will increase; meanwhile, Treg
ronment [186, 187]. Therefore, the use of Notch signaling cells are also involved in this process [194, 195]. These find-
inhibitor DAPT can inhibit M1 macrophage polarization ings remind us that the interference strategy against IFN
and reduce Th17 cell response, thereby leading to the resto- may be effective for treating SS.
ration of the Th17/Treg ratio. After macrophage polarization, both macrophage sub-
The NF-κB signaling pathway also plays an essential role types exist in patients with primary Sjogren’s syndrome.
in the pathogenic mechanism of EAU. In mammals, the NF- M1 macrophages exist in the early stage of PSS, which gen-
κB family consists of five members, including RelA (p65), erate inflammatory factors such as TNF-α, IL-6, IL-1β, and
RelB, c-Rel, NF-κB1 (p50), and NF-κB2 (p52), which form IL-12 to play a proinflammatory role and further activate
various dimer complexes that regulate gene transcription CD4+ T cells to differentiate into Th1 cell lineage, leading
by binding to 10bp-specific sequences (-κB sites) on target to the occurrence and development of submandibular gland
genes [188]. Recent studies have found that galactose inflammation [198]. In an in vitro experiment based on a
lectin-3 is expressed in EAU and has a particular proinflam- rabbit animal model, M2 macrophages secrete IL-10 and
matory effect, and TD139 (galactose lectin-3 inhibitor) can TGF-β and other anti-inflammatory mediators, which con-
inhibit the activation of NF-κB P65 by downregulating the tribute to the regression of inflammation and tissue regener-
expression of TLR4/MyD88, thereby reducing M1 polariza- ation, and alleviate autoimmune lacrimal gland
tion and contributing to the treatment of EAU [189]. Simi- inflammation, thereby playing an anti-inflammatory role
larly, IMD-0354, an inhibitor of IKKβ, can also minimize [199]. When SS develops to the late stage of the disease,
Th1/Th17-mediated inflammation by inhibiting NF-κB p65 the chronic inflammation proceeds to irreversible salivary
in an animal model of EAU [190]. gland fibrosis, which is mainly mediated by M2 macro-
In addition to the Notch and NF-κB signaling pathways phages. The TGF-β signal transduction pathways that
described above, PI3K/AKT/FOXO1 phosphorylation is induce fibrosis are divided into SMAD regulation and non-
also considered novel pathogenesis of EAU, and SMAD regulation. TGF-β can promote M2 macrophage
phosphodiesterase-4 inhibitors (apremilast, PDE4i) can polarization by activating SMAD2/3/4 trimer complexes,
reduce the Th1 and Th17 frequencies by inhibiting the and this pathway can also promote fibroblast-to-
downstream transcription factor FOXO1 expression in the myofibroblast transformation [200]. Non-SMAD pathways
PI3K/AKT pathway and enhancing the Treg cell response can activate the MAPK/RAS signaling pathway. RREB1, a
to alleviate EAU [191]. Interestingly, ICA combined with molecular junction between RAS and TGF-β pathways, can
peroxidase-3 (PRDx3) can downregulate H2O2 and activate also induce development and fibrosis [201–203]. It has been
the GPX4/SLC7A11/ACSl4 pathway, which may regulate confirmed that multiple pathways and signaling molecules
the transfer of macrophage polarization from M1 to M2, are involved in the pathogenesis of PSS inflammatory
exhibiting a specific therapeutic potential for EAU [192]. response. For example, researchers have found that metfor-
min could reduce mTOR by inhibiting the activation of 5′
3.6.8. Macrophage Polarization and Sjogren’s Syndrome. adenosine monophosphate-activated protein kinase
Sjogren’s syndrome (SS) is a chronic autoimmune disease (AMPK), reduce the production of antibodies after STAT3
commonly occurring in middle-aged women. Clinically, SS phosphorylation of B cells, promote T cell differentiation
can be divided into primary and secondary SS. Primary SS into Treg, enhance anti-inflammatory immunity, and thus
refers to the separate onset of SS, and secondary SS is mainly improve salivary gland function, suggesting that mTOR
induced by SLE and RA. The clinical manifestations of SS may be a promising therapeutic target [204]. In addition,
12 Mediators of Inflammation

TGF-𝛽, IL-6,
Interferon Jagged 1, 2 IL-17, IL-22
Delta 1, 3, 4 PAMPs, DAMPs LPS IL-4

Notch 1-4 TLR4 RPTK IL-4R TGF-𝛽RI/II

miR-155 JAK MyD88 Tocilizumab JAK

PI3K
miR-382
IRAK
SOCS-1 STAT1 NICD miR-467f miR-221-3P P38MAPK
miR-93 miR-466q PIP2 PIP3 SMAD2/3
miR-146a RAF
TRAF6 AKT
miR-21 High
CXCL10 RBP-J Lnc GBP9 P
miR-654
TAK1 TAB2 Lnc MIR31HG SMAD2/3 RAS
STAT3 SOCS3 STAT6 SMAD4
P38 IKKs MAPK P
AKT P
SGK1 MEK1/2
KLF4 SMAD2/3
NF- 𝜅B JNK PPAR- 𝛾 SMAD4
AKT2 mTOR AKT1 ERK1/2
P65/P50 P50/P50 AP-1

IRF3
Fibronectin
collagen type I
I-IFN

M2
M1 Salivary gland fbrosis

Decreased
ROS Proinfammatory factor iNOS PDGF, VEGF Anti-infammatory factor
Pathogen vasodilation
(TNF-𝛼, IL-1𝛽, IL-6, IL-12) (IL-10, TGF-𝛽)
removal

Oxidative Tissue repair, Myelin and axon repair Remission of

Tissue Submandibular gland infammation
damage angiogenesis rheumatoid arthritis
damage Nervous system infammation
Kidney infammation Remission of multiple sclerosis

Activate

Inhibit

Figure 1: A schematic illustration of the relationship between macrophage polarization-associated signaling pathways and autoimmune diseases.

IL-21 will increase PSS, which can induce the phosphoryla- 3.6.9. Macrophage Polarization and Systemic Sclerosis. Sys-
tion of STAT1 and STAT3 through the JAK/STAT pathway temic sclerosis (SSc) is an autoimmune disease in which
and promote the proliferation of Th17 cells, thereby playing chronic progressive inflammation and fibrosis of tissues
a certain role in the pathogenesis and treatment of PSS and organs are the main lesions after excessive extracellular
[205]. Other studies have revealed that activation of mTOR matrix production [208]. The pathogenesis of SSc is
can induce Th17 differentiation and inhibit the Treg effect unknown, but its pathogenesis involves activating various
through the PI3K/AKT pathway, and Th17/Treg imbalance immune cells, including macrophages. The disease may
aggravates inflammation and induces apoptosis [205]. Nev- involve proinflammatory M1 macrophages and profibrotic
ertheless, other researchers confirmed that PI3K/AKT can M2 macrophages with activation copathogenic disease
also alleviate SS symptoms. HUC MSCs can promote M2 [209–211]. Patients with SSc are predominantly inflamma-
macrophage polarization by activating PI3K/AKT pathway, tory lesions in the early stage, followed by extensive fibrosis,
thereby inhibiting the inflammatory response of autoim- cytoskeletal rearrangement, ECM remodeling, increased
mune lacrimal gland inflammation [199]. In addition, type I collagen, fibronectin, and α-SMA, including FN1
TLR2 and TLR4 expression is found to be increased in pri- (the gene encoding fibronectin) expression and TGF-β sig-
mary Sjogren’s syndrome, and MAPK and NF-κB are acti- naling pathway [212]. After TGF-β activation, macrophages
vated by MyD88, which induces M1 macrophage and fibroblasts can activate each other, further increasing tis-
polarization to secrete inflammatory factors. Therefore, sue thickness and hardness and mediating fibrosis [213].
blocking this pathway has a particular therapeutic effect on Various studies are currently aimed at regulating macro-
SS [206, 207]. phage polarization to improve SSc symptoms. The adeno-
The role of macrophage polarization balance in the path- sine deaminase of RNA can promote M1 macrophage
ogenesis of SS cannot be ignored. Still, in recent years, the activation at the beginning of SSc and control the release
research on SS has mainly focused on the pathogenesis of of inflammatory mediators (iNOS, IL-β) by regulating the
epithelial cells. Hence, the relationship between macrophage NF-κB signaling pathway, so ADAR1 deficiency in macro-
polarization and the molecular mechanism of SS remains to phages can significantly improve skin and lung sclerosis
be further explored. [214]. In addition, methyl-CpG-binding domain 2 (Mbd2)
Mediators of Inflammation 13

selectively binds to the SH2-containing inositol 5′-phos- a more comprehensive understanding of the relationship
phatase (Ship) promoter in macrophages and inhibits Ship between macrophage polarization and the occurrence and
expression, thereby inhibiting PI3K/AKT signaling and sup- development of autoimmune diseases can find more effec-
pressing M2 macrophages, so exogenous delivery of Mbd2 tive therapeutic targets for autoimmune diseases. It is also
can protect mouse models from fibrosis damage [215]. the focus of people’s efforts in the future.
Therefore, the ideal drug should be able to block the macro-
phage polarization pathway and reduce the activated macro-
Conflicts of Interest
phage to achieve combined anti-inflammatory and
antifibrotic effects. Still, the current research mainly focuses The authors declare no conflict of interest.
on regulating a macrophage, which has certain limitations in
disease treatment. It may be that the future development of
drugs that jointly inhibit M1 and M2 macrophages is a Authors’ Contributions
potential route to be explored.
D.G. and Y.P. conducted the conceptualization; J.H. and
Taken together, macrophage polarization plays an essen-
R.Q. conducted the investigation; Y.P. wrote the original
tial role in autoimmune diseases. In addition to the above-
draft preparation; D.G. wrote, reviewed, and edited the
mentioned autoimmune diseases, macrophage polarization
paper; M.Z. and H.Y. conducted the visualization; H.B. and
imbalance also occurs in ulcerative colitis, nonalcoholic liver
Y.Q. conducted the supervision. All authors have read and
disease, autoimmune diabetes, and other autoimmune dis-
agreed to the published version of the manuscript.
eases [216–218]. In the process of driving the polarization
of M1 and M2 macrophages, there are many signaling path-
ways involved, including the JAK-STAT, MAPK, TGF-β/ Acknowledgments
SMAD, Notch, and PI3K-AKT pathways (Figure 1). There-
fore, a deep understanding of the mechanism of macrophage This study was supported by the Key Project of Natural Sci-
polarization in the occurrence and development of autoim- ence Foundation of Shandong Province (ZR2020KC024 and
mune diseases can provide new insight into clinical treat- ZR2017LH042) and the National Natural Science Founda-
ment of autoimmune diseases by regulating macrophage tion of China (no. 81873163).
polarization balance.
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