cells

Review
Role of the Skin Immune System in Wound Healing
Angela Cioce, Andrea Cavani, Caterina Cattani and Fernanda Scopelliti *

National Institute for Health, Migration and Poverty INMP/NIHMP, Via di S.Gallicano, 25, 00153 Rome, Italy;
[email protected] (A.C.); [email protected] (A.C.); [email protected] (C.C.)
* Correspondence: [email protected]; Tel.: +39-06-55851305

Abstract: Wound healing is a dynamic and complex process, characterized by the coordinated
activities of multiple cell types, each with distinct roles in the stages of hemostasis, inflammation,
proliferation, and remodeling. The cells of the immune system not only act as sentinels to monitor
the skin and promote homeostasis, but they also play an important role in the process of skin
wound repair. Skin-resident and recruited immune cells release cytokines and growth factors that
promote the amplification of the inflammatory process. They also work with non-immune cells to
remove invading pathogens and debris, as well as guide the regeneration of damaged host tissues.
Dysregulation of the immune system at any stage of the process may lead to a prolongation of the
inflammatory phase and the development of a pathological condition, such as a chronic wound. The
present review aims to summarize the roles of different immune cells, with special emphasis on the
different stages of the wound healing process.

Keywords: skin; immune system; wound healing; wound repair

1. Wound Healing Overview

Wound healing involves a series of coordinated and overlapping cellular events and is
a complex and dynamic process. It is classically simplified into the following four main
phases: hemostasis, inflammatory response, proliferation, and dermal remodeling [1,2].
Citation: Cioce, A.; Cavani, A.; Hemostasis, the first step in the wound healing process, stops bleeding after vascular
Cattani, C.; Scopelliti, F. Role of the damage. Hemostasis begins with the vasoconstriction of vessel walls, followed by platelet
Skin Immune System in Wound aggregation and platelet plug formation (primary hemostasis). Next, the coagulation
Healing. Cells 2024, 13, 624. cascade is activated, converting soluble fibrinogen into insoluble filaments that form the
https://doi.org/10.3390/ fibrin network (secondary hemostasis). The platelet cap and fibrin network join together
cells13070624 to form the thrombus, which stops the blood flow [3]. The inflammatory phase is typified
by the strong involvement of resident and recruited cells of the innate and adaptive im-
Academic Editors: Simona Martinotti
and Elia Ranzato
mune system. This phase is concomitant with hemostasis and aims to clean wounds of
pathogens and debris. Following injury, resident skin cells are exposed to danger signals,
Received: 25 January 2024 like pathogen-associated molecular patterns (PAMPs) and danger-associated molecular
Revised: 21 March 2024 patterns (DAMPs) [4]. Damaged cells at the wound edge also release endogenous molecules
Accepted: 31 March 2024 that act as DAMPs, which are recognized by cellular pattern recognition receptors (PRRs),
Published: 4 April 2024 such as Toll-Like Receptors (TLRs), and provide danger signals aimed at alerting the im-
mune system [5]. DAMPs include DNA debris, as well as cytoplasmic molecules released
by dead cells. The interaction of TLRs with PAMPs or DAMPs activates several intracellular
signaling pathways that produce inflammatory cytokines, such as TNF-α and IL-1; antimi-
Copyright: © 2024 by the authors.
crobial molecules; and chemokines, such as CXCL1, CXCL5, and CXCL8 [6]. Two important
Licensee MDPI, Basel, Switzerland.
This article is an open access article
pathways activated as a consequence of skin barrier disruption are p44/42 MAPK and
distributed under the terms and
p38 MAPK, which initiate a cascade of signaling pathways involved in the early phases
conditions of the Creative Commons of the healing process [7]. Another pathway activated is that of the SAPK/JNK kinase,
Attribution (CC BY) license (https:// which plays an important role in the regulation of pro-inflammatory responses. By phos-
creativecommons.org/licenses/by/ phorylating a number of signaling molecules, it regulates gene expression and survival, as
4.0/). well as cellular metabolism [8]. After injury, keratinocytes also release pro-inflammatory

Cells 2024, 13, 624. https://doi.org/10.3390/cells13070624 https://www.mdpi.com/journal/cells

Cells 2024, 13, 624 2 of 13

cytokines that stimulate the migration and proliferation of neutrophils and macrophages at
the wound site, such as TNF-α, IL-1, IL-6, and IL-8 [9]. In a normal skin wound healing
process, inflammation usually lasts for 2–5 days and ends once the harmful stimuli are
removed [10].
As the inflammation recedes, the proliferation phase begins. This phase is character-
ized by the re-epithelialization of the wound, the development of new blood vessels, and the
formation of granulation tissue, which consists of large numbers of fibroblasts, granulocytes,
macrophages, blood vessels, and collagen bundles and partially reconstitutes the structure
and function of the damaged skin. Signals such as nitric oxide, cytokines, and growth
factors, released by several cell types at the site of injury, stimulate re-epithelialization.
During this phase, keratinocytes at the wound edges and epithelial stem cells from hair
follicles begin to proliferate and migrate to cover the wound. The migration process stops
when cells contact each other and form new adhesion structures [11]. This results in a thin
epithelial layer that covers the wound [12]. Additionally, growth factors such as vascular
endothelial growth factor (VEGF-A), platelet-derived growth factor (PDGF), and basic
fibroblast growth factor (bFGF) stimulate angiogenesis. At this stage, endothelial cells pro-
liferate to form new vessels that can deliver oxygen and nutrients to the damaged site [13].
In addition to their reactivity to growth factors, endothelial cells have other receptors that
promote angiogenesis. In case of injury, endothelial cells express receptors on their surface,
such as P-selectin, E-selectin and adhesion molecules ICAM-1 and VCAM-1, that promote
adhesion and the infiltration of leukocytes at the damaged site. Studies have shown that
deletion of P-selectin, E-selectin, ICAM-1, or VCAM-1 inhibited both neovascularization
and wound healing, thus stressing the importance of endothelial cell–leukocyte interactions
during skin repair [14,15].
Remodeling is the last step of the healing process, leading to wound maturation.
During this phase, the neo-vascularization regresses and the granulation tissue is replaced
by scar tissue. Granulation tissue is composed mainly of type III collagen, which is then
replaced by type I collagen, the primary component of healthy skin [3]. This process is
achieved through a balance between the synthesis of type I collagen and the degradation of
type III collagen, which results in ECM remodeling [16].
Both resident and recruited immune cells have active functions in the repair of skin
wounds. The present review aims to summarize the roles of the key players of the immune
system in the different stages of the wound healing process.

2. Skin Immune System Overview

The skin is the largest organ of the human body and serves as the first line of defense
against infection. Its main functions include protecting the host from danger signals
through physical barriers, the release of biomolecules, and the interaction between the
resident and recruited cells that constitute the so-called skin immune system [17,18].
The skin consists of the following two distinct structural layers: the epidermis and the
dermis [17]. The epidermis is a stratified, keratinized epithelium, the outermost layer of
which consists of corneocytes that are cemented together by intercorneocyte lipids. This
layer serves as a physical barrier, preventing the entry of chemicals and pathogens [19].
The dermis is a highly vascularized tissue containing hair follicles, nerve endings, and
secretory glands. It is composed of fibroblasts, which produce extracellular matrix (ECM)
proteins that give the skin its elasticity and strength [20]. Antimicrobial peptides (AMPs),
such as defensins, are acidic in PH and contribute to the skin’s protective functions, because
they make the skin an inhospitable environment for potential pathogens [21]. Importantly,
the skin contains both resident and recruited immune cells, including mast cells, dendritic
cells (DCs), lymphocytes, and macrophages. Resident and recruited cells form the skin
immune system, which acts as an integrated sentinel device, constantly monitoring the
skin and promoting the maintenance of homeostasis [22]. In case of injuries, immune
cells from peripheral blood are recruited to the damaged area and interact with resident
cells, thus activating a cascade of events intended to eliminate the insult and repair the
Cells 2024, 13, 624 3 of 13

wound. Keratinocytes and melanocytes, along with recruited immune cells, play crucial
roles in establishing an adequate immune response against potential pathogens. This
occurs both in the early stages after skin injury and later on, participating in the amplifi-
cation of the inflammatory response. The bacteria that colonize wounds belong mainly
to the families of Staphylococcaceae and Pseudomonaceae. In particular, Gram-negative
bacteria belonging to the Staphylococcus genera are the first to invade wounds, followed
by Gram-negative bacteria, such as Pseudomonas spp., E. coli, Klebsiella pneumoniae and
Enterobacter spp. Once in the wound, these bacteria release microbial products that pro-
mote their survival and persistence in the host. It has been observed that their presence
contributes to the prolongation of the inflammatory phase, the development of infection,
and delays in the healing process. Therefore, it is essential to prevent the entry of these
pathogens or clean the wound of them for successful wound closure [23]. Keratinocytes
have TLRs, which recognize the PAMPs typical of pathogenic organisms. Once triggered,
TLRs activate second messengers, such as inflammasomes and NFkB proteins. Moreover,
keratinocytes release various pro-inflammatory cytokines, such as IL-1, IL-6, INF-γ, and
TNF-α, as well as chemokines, such as CCL27, which are essential for the activation and
recruitment of immune system cells [24]. Melanocytes also express a variety of TLRs,
including TLR1, TLR2, and TLR6. Melanocytes regulate the immune response by releasing
Cells 2024, 13, x FOR PEER REVIEW
cytokines, such as IL-figβ, IL-6, TNF-α, and chemokines, such as CCL2 and CCL3, 4which of 19

are involved in leukocyte recruitment. Additionally, melanocytes promote the phagocytosis

of pathogens [25] (Figure 1).

Figure 1. Representation of the roles of skin immune system cells in the different stages of the
wound healing.
Figure 1. Representation of the roles of skin immune system cells in the different stages of the wound healing.

3. Role of Skin Immune System in Hemostasis

Cells 2024, 13, 624 4 of 13

3. Role of Skin Immune System in Hemostasis

3.1. Platelets
The platelet is the main cell involved in this process. Platelets are nucleated cells
that are derived from megakaryocytes, do not interact with endothelial cells, and circulate
preferentially near the vessel wall under physiological conditions. In fact, the integrity of
the endothelial coating provides a barrier that prevents platelet activation and aggregation.
This is due, in part, to the release of substances such as nitric oxide and prostacyclins [26].
Following tissue injury and microcirculation disruption, damaged cells release vaso-
constrictors, such as endothelin, to reduce bleeding. Vasoconstriction is also regulated by
circulating catecholamines, epinephrine, norepinephrine, and prostaglandins [3]. Simulta-
neously, platelets adhere to the damaged endothelium through the interaction between the
platelet receptor GPIb-IX-V and the collagen-bound von Willebrand factor (vWF). Hemosta-
sis initiates platelet activation, leading to the generation of thrombin, which contributes
to the formation of a hemostatic plug. In particular, thrombin binds to PAR1 and PAR4
receptors [27], stimulating platelets.

3.2. Platelets and Inflammation

In addition to their well-characterized role in hemostasis, platelets play important roles
in immunity and inflammation. Indeed, in the hemostatic plug, activated platelets release
a plethora of cytokines and chemokines that promote the recruitment of immune system
cells and regulate subsequent steps in the healing process [28]. In particular, platelets
have three distinct types of cytoplasmic granules, containing more than 300 molecules,
including platelet factor 4 (PF4), epidermal growth factor (EGF), platelet-derived growth
factor (PDGF), IL-1, IL-6, and TGF-β, as well as chemokines, such as CXCL1, CXCL8,
CCL3 CXCL4, CXCL5, and CXCL7 [29]. Platelet factor 4 is a chemotactic factor for neu-
trophils, monocytes, and fibroblasts, and it promotes the differentiation of monocytes
into macrophages [30]. PDGF leads to the induction of chemotaxis and the prolifera-
tion of immune cells, promoting the formation of new blood vessels and granulation
tissue [31]. TGF-β1 stimulates keratinocyte proliferation, as well as the remodeling and
regeneration of the epidermal layer [32]. IL-1 and IL-6 activate the complement cascade
and C5, increasing vascular permeability and stimulating the migration of neutrophils and
macrophages [33,34].
The chemokine CXCL4 promotes neutrophil activation, including adhesion and de-
granulation, and contributes to the differentiation of monocytes recruited to the site of skin
injury into macrophages [35]. Additionally, CXCL4 and CCL5 increase the adhesiveness
of circulating monocytes to the endothelium of the dermal microvasculature [36]. CXCL7
is the most abundant platelet-derived chemokine. Upon proteolytic cleavage, CXCL7 is
cleaved into the following four chemokines: PBP, CTAP-III, β-TG, and NAP-2. However,
only NAP-2 has chemotactic activity [37]. Releasing pro-inflammatory molecules, platelets
are indeed the initiators of the inflammatory phase of tissue repair. Hemostatic plug forma-
tion and immune cell recruitment, mediated by activated platelets, prevent the invasion of
microbial agents into the bloodstream. In addition, recent studies suggest that platelets also
play a role in linking innate and adaptive immune responses. Activated platelets express
intracellular MHC class I molecules on their surface and, together with other molecules re-
quired for synapse formation with T cells, such as the costimulatory molecule CD86, could
present antigens and promote T-cell activation [38]. In the case of viral infection, mouse
platelets were shown to modulate adaptive immune responses both in vivo and in vitro.
The immune response to adenovirus was attenuated in platelet-depleted mice, but improve-
ments in humoral and cellular responses were observed following platelet infusion [39].
Accordingly, in vitro studies have indicated that platelet-derived biomolecules, such as
platelet lysate (PL), promote tissue repair and facilitate the process of wound healing by
stimulating macrophage polarization in the M2-like phenotype. In fact, platelet lysate
reduced the expression of costimulatory molecules CD80 and CD86, decreased secretion
Cells 2024, 13, 624 5 of 13

of the pro-inflammatory cytokine TNF-α, and increased secretion of TGF-β, a cytokine

involved in the regenerative phase of the healing process [40].
Additionally, platelet derivatives could induce a transient increase in Th1 cytokines,
followed by an expansion of TGF-β+ T regulatory cells, which promote tissue regenera-
tion [41].

4. Role of the Innate and Adaptive Immune Cells in the Inflammatory and Proliferative
Phases of Wound Healing
4.1. Neutrophils
Neutrophils are the first immune system cells to migrate to the injury site, and they
remain the most abundant cell type in the first 24 h. Their primary function is to degrade
and eliminate pathogens by releasing antimicrobial substances, reactive oxygen species
(ROS), and proteases, contained in cytoplasmic granules [33]. During the neutrophil
maturation process, various granules are formed, including azurophil granules (primary
granules) and secondary granules. The primary granules are rich in peroxidase, azurocidin,
lysozyme, and defensins, while the secondary granules are rich in lactoferrin, as well as
metalloproteases such as MMP-8 and cathelicidin (hCAP-18), an antimicrobial protein. Due
to the functional diversity of granular substances, neutrophils target pathogens through
different mechanisms. For example, defensins act by creating pores on bacterial membranes.
Lactoferrin interacts with iron-dependent metabolic pathways, while azurocidin enhances
bacterial wall permeability [42].
MMPs function by degrading extracellular matrix components and facilitating the
migration of immune system cells from circulation to the site of injury. Although MMPs
play a critical role in the repair process, several clinical studies indicate that overproduction
of metalloproteases increases damage at the lesion site, leading to prolonged inflammation
and impaired wound healing [43]. Neutrophils strengthen their antimicrobial capabilities
by releasing neutrophil extracellular traps (NETs), which consist of nuclear chromatin,
decorated with proteins, typically confined to their granules. The cationic component of
NETs enables electrostatic bonding with the microorganisms’ surfaces, exposing them to
high local levels of cytotoxic molecules. In addition, experiments conducted on primary
human neutrophils have shown that NETs indirectly augment the complement’s capacity
to destroy pathogens [44]. Although NETs can protect the host from microbes, excessive
production can be harmful, because they protract the inflammatory process and delay
wound healing. Recent studies with in vitro experiments and animal models have shown
that NETs play a crucial role in the pathogenesis of some metabolic, autoimmune, and
auto inflammatory diseases, as well as in some septic conditions that increase morbidity
and mortality [45]. Neutrophils are important in the wound repair process, not only for
their ability to eliminate pathogens, but also for their ability to release substances that
amplify the inflammatory process. Several studies have shown that activated neutrophils
overexpress genes involved in the healing process. Specifically, activated neutrophils hyper-
express cytokines and chemokines (TNF-α, IL-1β, IL-6, CXCL2, CXCL8, and VEGF-A)
which promote inflammatory response, stimulate fibroblast and keratinocyte proliferation,
and promote angiogenesis [46]. In a normal healing process, the neutrophils at the wound
site undergo apoptosis after fulfilling their functions. Macrophages phagocytose apoptotic
neutrophils, strongly signaling inflammatory resolution. In fact, excessive neutrophil
activity and persistence at the wound site results in a prolonged inflammatory state and
the development of a chronic wound [43] (Figure 2).
 Cells 2024, 13, x FOR PEER REVIEW 7 of 19

Cells 2024, 13, 624 6 of 13

Figure 2. Consequences of abnormal immune cell activity on the healing process.

4.2. Macrophages
Macrophages are critical for wound healing and tissue regeneration. In intact skin,
Figure 2. Consequences
resident of abnormal
macrophages function asimmune cell activity
homeostatic on the healing process.
sentinels.

4.2. Macrophages 4.2.1. M1 Macrophages

In case of skin injury, PAMPs and DAMPs stimulate the polarization of resident
Macrophages are critical for woundinto
macrophages healing andpro-inflammatory
the M1 tissue regeneration. In intact[47].
phenotype skin,M1
resident macrophages
macrophages, function as
also known
as “classically activated macrophages”, support the inflammatory process by releasing
homeostatic sentinels.
cytokines such as IL-1β, IL-12, TNF-α, IL-6, and IL-23, which prevent pathogen passage and
alarm the adaptive immune system [48]. M1 macrophages can activate T lymphocytes due
4.2.1. M1 Macrophagesto the abundance of MHC class I and class II molecules, as well as CD80/CD86 costimula-
tory molecules, on their surface [47,49]. Furthermore, M1 macrophages prevent infection by
In case of skin injury,phagocytosing
PAMPs and DAMPspathogenstimulate the polarization
phagosomes of resident
rich in reactive oxygen macrophages
species (ROS)into
[50].the M1 pro-
Proinflam-
matory macrophages also secrete metalloproteinases, including MMP9, which
inflammatory phenotype [47]. M1 macrophages, also known as “classically activated macrophages”, support degrade thethe
extracellular matrix and fibrin thrombus, thus promoting their migration. Digested ECM
inflammatory process by releasing cytokines such as IL-1β, IL-12, TNF-α, IL-6, and IL-23, which prevent pathogen
fragments act as immunostimulatory DAMPs, aggravating the proinflammatory state of
passage and alarm thethe adaptive
woundimmune system [48].
[51]. In addition M1 macrophages
to being can activate also
bactericidal, macrophages T lymphocytes due to the
carry out efferocytosis,
abundance of MHC class I and class II molecules, as well as CD80/CD86 costimulatory molecules, on
a multi-step process by activated macrophages aimed at removing apoptotic their
cells, surface
such
as neutrophils, after their internalization and digestion, which that is very important to
[47,49]. Furthermore, M1 macrophages prevent infection by phagocytosing pathogen phagosomes rich in reactive
eliminating neutrophils and resolving inflammation.
oxygen species (ROS) [50]. Proinflammatory macrophages also secrete metalloproteinases, including MMP9,
4.2.2. M2 Macrophages
which degrade the extracellular matrix and fibrin thrombus, thus promoting their migration. Digested ECM
As the
fragments act as immunostimulatory inflammatory process subsides,
DAMPs, aggravating macrophages state
the proinflammatory switch
of from an inflammatory
the wound [51]. In addition
phenotype to an M2 anti-inflammatory phenotype. M2 macrophages, also called “alterna-
to being bactericidal, tively
macrophages also carry out efferocytosis, a multi-step process by activated macrophages
activated macrophages”, express anti-inflammatory mediators such as IL-10, TGF-β,
aimed at removing apoptotic
VEGF-A,cells,
and such
IGF1.asThey
neutrophils, after their
also promote internalization
fibroblast and digestion,
proliferation, which that
ECM synthesis, andisan-
very
important to eliminating neutrophils
giogenesis [52].and
Theresolving
transitioninflammation.
from M1 to M2 is crucial for resolving inflammation and
shifting the balance toward tissue repair [53]. Neutrophil phagocytosis also facilitates this
conversion. Indeed, the impairment of efferocytosis in diabetic wounds and aged mice
4.2.2. M2 Macrophages
prolongs the inflammatory phase and delays healing [54]. In the proliferative phase, M2
macrophages release TGF-β, VEGF-A and other cytokines that trigger the transition from
fibroblast to myofibroblast [55]. Myofibroblasts release metallo-proteinases that degrade
Cells 2024, 13, 624 7 of 13

the provisional matrix and synthesize ECM components, such as fibronectin, collagen, and
proteoglycans [1]. This process contributes to the formation of granulation tissue, which
serves as a scaffold for wound cell migration and differentiation, in addition to support-
ing the formation of new blood vessels [56]. In contrast, certain inflammation mediators
released by M1 macrophages, including TNF-α, inhibit differentiation, confirming that pro-
longed inflammation results in delayed wound closure [3]. In addition, cytokines released
by M2 macrophages, such as PDFG, VEGF-A, and TGF-β, promote the formation of new
capillaries in endothelial cells, which are needed to transport oxygen and nutrients, as well
as to enable tissue regeneration [57]. Angiogenesis, the process of new blood vessel for-
mation, is essential for successful wound healing [58]. After the re-epithelialization phase,
macrophages regain their phagocytic phenotype and transform into a subgroup known
as M2c. M2c macrophages release proteases, phagocytose cells, and matrix components
that are no longer necessary for the healing process. Several pathologies are associated
with altered macrophage activity. Delayed macrophage influx can result in delayed effe-
rocytosis, resulting in accumulated neutrophils, extracellular matrix proteins, and debris
in the wound, which can cause a chronic inflammatory state [3]. Conversely, excessive
macrophage activity in the final stage of the repair process overstimulates fibroblasts, with
subsequent accumulation of extracellular matrix proteins and formation of fibrotic scars [1].

4.3. Mast Cells

Mast cells (MCs) are immune system cells that originate from CD34+/CD117+ bone
marrow progenitor cells. They are involved in inflammatory processes and allergic reactions
through the release of mediators stored in cytoplasmic granules [59]. When an injury occurs,
a variety of mediators, such as monocyte chemoattractant protein-1 (MCP-1), released
from keratinocytes recruit mast cells to the injured site [60]. Once activated, mast cells
release vasoactive and proinflammatory mediators. These include histamine, tryptase,
TNF-α, VEGF-A, IL-6, and IL-8. Tryptase binds to protease-activated receptor 2 (PAR2)
on endothelial cells and, together with histamine, induces vasodilation by promoting the
infiltration of neutrophils and inflammation mediators at the site of injury [61]. Histamine
also promotes the antibacterial activity of keratinocytes. This is achieved by enhancing the
expression of pathogen recognition receptors, such as TLR-2, and increasing their GM-CSF
production by promoting macrophage maturation. Additionally, IL-8, released by MCs, is
involved in neutrophil chemotaxis. Tryptase, also released by MCs, promotes the migration
and proliferation of fibroblasts and stimulates the release of ECM proteins [62]. Thus, mast
cells release mediators that are relevant not only in the inflammatory phase, but also in the
later stages of the wound healing process [63].

4.4. T-Cell Populations

4.4.1. Th1 Lymphocytes
In the inflammatory phase of the healing process, cytokines released in the microen-
vironment recruit Th1 lymphocytes to the wound site, which play an important role in
this phase. In fact, Th1 lymphocytes produce pro-inflammatory cytokines, such as IL-2,
which acts as a survival signal for T-reg, T helper, and cytotoxic T cells, and IFN-γ [64].
Although IFN-γ has potential antifibrotic effects, it is also a proinflammatory cytokine.
IFN-y knockout mice had reduced inflammation but increased fibrosis, highlighting that
inflammation and fibrogenesis are not always correlated [65]. Th1 cells also support the
inflammatory process by promoting macrophage polarization into the M1 phenotype. In
turn, M1 releases cytokines that promote Th1 aggregation at the injury site [66]. As the
inflammatory phase subsides, the activity of Th1 decreases, and a reparative response
mediated by Th2 lymphocytes begins.

4.4.2. Th2 Lymphocytes

Th2 lymphocytes produce cytokines, such as IL-4, IL-5, IL-13, and IL-10, that promote
collagen production by fibroblasts. IL-13 and IL-4 are the main stimulators of ECM de-
Cells 2024, 13, 624 8 of 13

position through the activation of the intracellular JAK pathway. This pathway leads to
the phosphorylation of STAT6 and the activation of genes that promote collagen synthesis
(Table 1 and S1–S3). In addition, cytokines IL-4 and IL-13 induce macrophage polariza-
tion towards the M2 reparative phenotype. Studies on Th1 and Th2 have shown that
the transition from the type 1 inflammatory response to the type 2 reparative process is
fundamental for wound healing. This is because some fibrosis is intrinsically needed to
effectively resolve physiological wound healing [66].

Table 1. The main signaling pathways required in different phases of wound healing.

Wound Healing Phase Cell Type Cytokines Signaling Pathways

TNF-α NF-kB
IL-1β NF-kB
NEUTROPHILES
IL-6 STAT3
VEGF ERK
TNF-α NF-kB
IL-1β NF-kB
M1 MACROPHAGES IL-6 STAT3
INFLAMMATION IL-12 STAT4
IL-23 STAT4
TNF-α NF-kB
IL-6 STAT3
MAST CELL
VEGF ERK
IL-8 STAT3/ERK
INF-γ STAT1
TH1 LYMPHOCYTES IL-2 STAT3/ERK
IL-12 STAT4
IL-10 STAT3
TGF-β SMAD
M2 MACROPHAGES
VEGF ERK
PROLIFERATION IGF1 ERK
IL-4 STAT6
TH2 LYMPHOCYTES IL-5 ERK/NF-kB
IL-13 STAT6
IL-10 STAT3
REMODELING T-REG
TGF-β SMAD

4.4.3. Th17 and Th22 Lymphocytes

Several studies have shown that IL-22, produced by two subgroups of T lymphocytes
(Th17 and Th22), contributes greatly in repair processes. In particular, IL-22 stimulates
the formation of new blood vessels, granulation tissue, and keratinocyte proliferation,
promoting re-epithelialization [67]. Treating diabetic mice with IL-22 significantly accel-
erated diabetic wound closure to the levels of non-diabetic wounds. Specifically, IL-22
treatment was found to be associated with increased vascular density and granulation
tissue formation similar to those of nondiabetic wounds [68].

4.4.4. T-Reg Lymphocytes

Other immune cells, T-regs, are key players in reducing the inflammatory response
during the healing process [69,70]. In human skin, T-regs are inclined to exhibit a memory
phenotype, and they are localized in areas of the epidermis and dermis surrounding hair
follicles. These cells release cytokines, such as IL-10 and TGF-β, that stimulate macrophage
polarization into M2 and suppress the inflammatory response. Ablation of T-regs in
mouse excisional wound models leads to increased levels of IFN-γ and proinflammatory
macrophages, resulting in a prolonged type 1 inflammatory response and delayed wound
closure [66]. A recent study in Foxp3-DTR transgenic mice, where T-regs are depleted
Cells 2024, 13, 624 9 of 13

following injection with diphtheria toxin, found that the healing process was slower
in T-reg-depleted mice than in wild-type controls [9]. T-regs are also involved in the
pathological fibrosis of keloids, because they have been shown in vitro to upregulate
collagen expression by fibrocytes, which are myeloid-derived profibrotic cells. This increase
in collagen expression is mediated through TGF-β production by Tregs.

4.4.5. γδ T Lymphocytes
In mice, a population of epidermis-resident γδ T cells with dendritic morphology
(DETC) are involved in the maintenance of skin homeostasis and the promotion of wound
repair by releasing, upon activation, insulin-like growth factor-1 (IGF-1), granulocyte
macrophage colony stimulating factor (GM-CSF), IL-17, IL-13, and several chemokines
that sustain the survival of keratinocytes and promote leukocyte recruitment [71,72]. In
mice, it has been demonstrated that keratinocyte-released IL-15 regulates the production
of IGF-1 by γδ T cells. Specifically, blocking IL-15 leads to a reduction in IGF-1 secretion,
which delays the healing process. Furthermore, the involvement of T γδs in the repair
process is also mediated by the release of IL-17A, which promotes the release of epidermal
antimicrobial peptides, such as β-defensins, and chemokines, such as CCL3, CCL4, and
CCL5, which support the inflammatory process by recruiting immune cells [71]. Mice
lacking γδ T cells show delayed wound closure due to reduced keratinocyte proliferation,
delayed macrophage infiltration, and less deposition of ECM [73]. Although DECTs are
absent in humans, human skin harbors a population of gd T cells, equipped with a lim-
ited TCR repertoire, whose antigen specificity and role in wound healing is still largely
undefined [74].

4.5. Langerhans Cells and Dermal Dendritic Cells

Langerhans cells (LCs) are professional antigen-presenting cells of myeloid origin
resident in the epidermis. LCs constitutively express major histocompatibility complex
class I and II (MHCI/MHCII) molecules and present antigens to CD8+ and CD4+ T lym-
phocytes [75]. The LC membrane is rich in structures that allow adhesion with T cells or
act as co-stimuli for T cell activation (CD80, CD86). Under homeostasis, Langerhans cells
persist in the epidermis through interactions between epithelial cell adhesion molecules
(EpCAMs), or E-cadherin expressed on LCs, and the E-cadherin exposed by keratinocytes.
When exposed to mediators of inflammation and other activators, such as PAMPs, LCs
migrate from the epidermis to the lymph nodes, where they activate the adaptive immune
response by deactivating the adhesion interaction between E-cadherin and EpCAM [22].
In particular, the migration of LCs through the dermis is mediated by CXCR4 signaling
after binding to the chemokine CXCL12, which is produced by dermal fibroblasts [76].
In injured skin, endogenous alarmins, cytokines produced by damaged cells, and other
inflammatory signals, such as PAMPs, stimulate the recruitment, activation, and maturation
of LCs. Activated LCs increase the expression of MHC-II molecules and promote T-cell
activation [77]. LCs also express C-type lectin Langerin (CD207), which is involved in the
formation of Birbeck granules.
The role of LCs in the wound repair process has not been widely explored, but several
data suggest that LCs could inhibit proliferation in the epidermis. Increased LC density has
been observed in chronic [78] and hypertrophic wounds [79]. Depletion of LCs promotes
keratinocyte proliferation, granulation tissue, and new blood vessel formation in Langerin
DTR transgenic mice. In fact, the wounds of Langerin DTR transgenic mice healed faster
than those of the control group, indicating a suppressive role of LCs in regulating cutaneous
wound healing [80]. Dermal dendritic cells (dDCs) migrate to lymph nodes and present
antigen to T cells, similar to LCs. Dermal dendritic cells are classified into the following
two main groups: conventional dendritic cell type one (cDC1) and conventional cell type
two (cDC2). In contrast to murine cDC1, human dermal dendritic cells do not express
Langerin [22]. The cDC1 (141+) co-expresses CD304 (neuropilin-1), XCR1, and CD370,
and activates a Th1 immune response. On the other hand, cDC2 co-expresses CD11b and
Cells 2024, 13, 624 10 of 13

CX3CR1, and activates a Th2 response. Immature dermal dendritic cells express pattern
recognition receptors, such as TLR2, TLR4, CD206, and CD209. In contrast, mature dermal
dendritic cells express high levels of costimulatory molecules, such as CD83, and lower
levels of pattern recognition receptors. Activated dermal dendritic cells participate in
the inflammatory response by releasing cytokines, such as TNF-α, and chemokines that
contribute to the elimination of infectious agents. However, in some cases, their activation
underlies a pathological tissue response with persistent inflammation [81]. Other dendritic
cells are plasmacytoid dendritic cells (pDCs), which are present in the skin exclusively
under inflammatory conditions [82]. The pDCs produce high amounts of INF-α. Depletion
of pDCs in mice treated with bleomycin, which induces skin fibrosis, showed a decrease in
skin thickness and collagen content compared to those in wild-type mice, suggesting a role
for pDCs in fibrosis [22]. Further studies are required to better define the role of DCs in the
wound repair process.

5. Role of Immune Cells in the Remodeling Phases of Wound Healing

Remodeling represents the last stage of the wound repair process and is character-
ized by the regression of angiogenesis, the replacement of type III collagen with type I
collagen, and the transition of granulation tissue into scar tissue. In addition, most of the
cells involved in the previous stages undergo apoptosis [57]. The main cells involved in
this phase are myofibroblasts and macrophages, which release MMPs promoting ECM
reorganization. In addition, macrophages present at the wound site assume a fibrolytic
phenotype, degrading excess ECM fragments and phagocytosing dead cells and debris. In
a normal repair process, at the end of the remodeling phase, myofibroblasts also undergo
apoptosis and are phagocytized by macrophages. Missed apoptosis of cells in granulation
tissue leads to the development of hypertrophic scars [3].

6. Conclusions and Future Directions

Cells of the innate and adaptive immune system cooperate with resident cells to
provide integrated and sometimes redundant mechanisms to ensure proper wound re-
pair. Dysregulation of immune cell activity at any stage of the process can lead to patho-
logical conditions such as chronic wounds, hypertrophic wounds, or keloids. Chronic
wounds, to date, represent an important cause of morbidity and mortality and are of
serious clinical concern. In fact, a characteristic feature of chronic wounds is the presence
of a chronic inflammatory process, due to a prolonged presence of pro-inflammatory cells
in the wound. In chronic or hypertrophic wounds, there is dysregulation in the production
of pro-inflammatory factors, such as TNF-α, IL-1, or IL-6, or anti-inflammatory factors,
such as IL-4, IL-10, or TGF-β. These cytokines, therefore, represent important therapeutic
targets, so strategies that modulate the immune system may be an innovative therapeutic
approach for the treatment or prevention of chronic wounds. However, it must be consid-
ered that modulation of the immune system may have negative effects at sites other than
the wound, or on other patient conditions, such as infections or allergies. Therefore, given
the high complexity of the healing process, it is essential to conduct further studies to better
understand the mechanisms underlying both normal and pathological healing.

Supplementary Materials: The following supporting information can be downloaded at: https://
www.mdpi.com/article/10.3390/cells13070624/s1, Table S1: GlyGly (K) Sites; Table S2: Quantitative
and differential analysis; Table S3: DiGly sites exclusively identified in one group.
Author Contributions: A.C. (Angela Cioce) wrote the article, A.C. (Andrea Cavani) contributed to
the implementation of the review, C.C. reviewed and edited the review, and F.S. contributed to the
design and writing of the manuscript. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Acknowledgments: We thank Angela Forese for the critical revision of the English language.
Cells 2024, 13, 624 11 of 13

Conflicts of Interest: The authors declare no conflicts of interest.

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