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Abstract

Barrier tissues like the skin, gastrointestinal tract, and respiratory system exhibit high IL-33 expression. IL-33 expression increases in humans and mice during cutaneous wound healing. Following skin injury, IL-33 alerts immune cells via its receptor ST2, modulating the inflammatory response and acting as a nuclear transcription factor to regulate target cell function. Multiple studies have verified the vital function of IL-33 in cutaneous wound healing; however, the mechanisms remain contentious. This review provides an overview of the progress made in comprehending the biological characteristics of IL-33, including its production, its regulatory effects on target cells’ activities, and its impact on chronic wounds. This overview aids in elucidating the mechanisms through which IL-33 contributes to wound healing, thereby offering insights into potential therapeutic strategies for treating chronic wounds.

Keywords

IL-33 ST2 wound healing inflammation

Introduction

As the body’s first line of defense, the skin directly interacts with the external environment and serves as a barrier to protect our internal organs. When the skin is damaged, it quickly initiates a series of complex repair mechanisms. These mechanisms aim to close the wound as soon as possible, and prevent the invasion of external pathogens. In clinical practice, wounds often fail to close promptlyfor various reasons. This can lead to the development of chronic non-healing wounds, including diabetic ulcers, pressure ulcers, and infected wounds.^1,2 Therefore, a comprehensive investigation into the cellular and molecular mechanisms involved in skin injury repair is crucial. This understanding is essential for effective wound management and the development of therapies to promote wound healing.

Traditional wound healing interventions have predominantly focused on enhancing the functionality of skin effector cells, such as epithelial and fibroblast cells, to facilitate the reparative process. However, recent studies have revealed that epithelial cell regeneration and repair are not entirely spontaneous but involve complex interactions between immune cells and epithelial cells.^3–5 Immune cells residing in skin tissue actively interact with surrounding stromal and epithelial cells to drive the repair process. This interaction involves a complex array of molecular regulatory networks.

Interleukin-33 (IL-33) is essential to type 2 immune response and has garnered attention for its role in tissue repair. Based on this,our review focuses on the regulatory effects of IL-33 on immune cells, as well as skin epithelial and stromal cells during cutaneous wound healing. The objective is to elucidate its potential mechanisms and therapeutic potential in promoting skin wound healing.

Overview of IL-33 and its receptor ST2

IL-33 is a pro-inflammatory cytokine identified in 2005. It is classified as a novel member of the IL-1 family due to its structural characteristics.^6,7 The full-length human IL-33 protein (IL-33FL) contains 270 amino acids and consists of three domains: a N-terminal chromatin-binding domain, a central domain, and a C-terminal receptor binding domain.⁸ The N-terminal domain comprises a highly conserved nuclear localization sequence (NLS), which consists of a chromatin-binding motif (CBM, aa40-56) and the core NLS (aa61-78). The CBM interacts with histones H2A and H2B, causing IL-33accumulation in the cell nucleus. The C-terminal domain harbors an evolutionarily conserved IL-1-like structure with an essential site for binding to the receptor ST2.⁹ The central domain contains numerous protease recognition sites that can be cleaved by inflammatory cell proteases, yielding a 18-21 kDa cleavage product. This substance, known as mature IL-33 (IL-33M), has 30-60 times the biological activity of IL-33FL (Figure 1).^11–14

Figure 1.

Structure of IL-33 and ST2. Full-length IL-33 has three domains: an N-terminal nuclear domain, a C-terminal receptor-binding domain, and a central domain. Proteases can cleave the central area to produce mature IL-33 (A)*. IL-33 binds to the ST2 on the cell membrane to act on target cells, whereas soluble ST2 (sST2) may function as a decoy receptor, inhibiting IL-33’s extracellular cytokine effect (B). *This figure is cited from Dwyer et al¹⁰ and has been modified.

IL-33 is mainly distributed in the nucleus of tissue-derived cells, including vascular endothelial cells, epithelial cells in barrier tissues, and fibroblasts in diverse tissues. Correspondingly, it often functions as a cytokine extracellularly and/or a transcriptional regulator intracellularly to impact diverse cells. When cell damage or necrosis is caused by infection, trauma, stress, or other stimuli, the affected cells quickly produce IL-33, which thereafter serves as an “alarmin” to notify the immune system of potential danger.^8,15

The IL-33 receptor, referred to as IL-1 receptor-related suppression of tumorigenicity 2 (ST2), is a member of the IL-1 receptor family. It is expressed in many types of stromal cells and almost all kinds of immune cells. Human ST2 has three isoforms: ST2L, a membrane-bound isoform with a cytoplasmic signaling domain; sST2, a soluble isoform without transmembrane and cytoplasmic signaling domain; and ST2V, a variant of sST2 expressed mainly in gut tissue. ST2L, when bound to IL-33, forms a complex with IL-1RAcP (IL-1 family accessory receptor ) to activate downstream signaling pathways such as NF-kB, and ERK1/2.¹⁰ The sST2 isoform, however, competes with IL-33 to inhibit the signaling acts as a “decoy receptor”. (Figure 1).

IL-33/ST2 in cutaneous wound healing

Transgenic/knockout mice studies

Various IL-33 and ST2 transgenic mouse strains were used in wound healing studies. Oshio et al. investigated IL-33 knockout (KO) mice and soluble ST2 (sST2) transgenic mice and discovered that IL-33KO mice exhibited a slower wound healing rate than wild-type (WT) mice.¹⁶ Because excessive sST2 can prevent IL-33 signaling and sST2 transgenic mice showed no significant difference in wound healing compared to WT mice, it seems that IL-33 promotes wound healing not dependent on the extracellular IL-33. The wound beds had more neutrophil infiltration and exhibited higher levels of inflammatory cytokines in IL-33 KO mice thanin WT mice, which indicated the appearance of an excessive inflammatory response during wound healing. An intraperitoneal injection of an NF-kB inhibitor in IL-33KO mice suppressed IL-6 overexpression and improved delayed healing, implying that nuclear IL-33 promotes wound healing by reducing pro-inflammatory cytokine production via NF-kB activation inhibition, thereby suppressing skin inflammation.¹⁶

However, the are studies showing a different perspective. Yin et al discovered thatintraperitoneal injection of IL-33 significantly accelerated wound healing in mice.¹⁷ IL-33 has been shown to promote epithelialization, increase collagen synthesis, enhance extracellular matrix deposition, and facilitate the alternative activation of macrophages (M2 macrophages)^18,19 Lee et al. found that animals with ST2 gene knockout displayed impaired wound healing as compared to WT mice showing delayed epithelialization, diminished angiogenesis, and immature collagen components. At day 4 post-wounding, the wounds of ST2 knockout mice exhibited a higher proportion of pro-inflammatory macrophages and a significant increase of neutrophils. Thus, it is believed that ST2 receptor signaling promotes macrophage transition from a pro-inflammatory to a repair-promoting phenotype, which then facilitates epithelialization, angiogenesis, and reducing scar formation.^20,21 These studies suggest that IL-33 harbors the potential to act as a cytokine to modulate cellular functions such as macrophages through the ST2 receptor, thus maintaining skin homeostasis and promoting wound healing.

The inconsistencies in these findings about whether its effects are primarily mediated through nuclear transcriptional regulation or acting as extracellular cytokine. Several factors may contribute to these discrepancies. First, interleukin-33 (IL-33) and its receptor, ST2, are widely expressed in various cell types. Their mechanisms of action on target cells differ among these cell types. In epithelial cells, IL-33 predominantly exerts its effects through nuclear transcriptional regulation. In contrast, in immune and stromal cells, it mainly functions as a cytokine that modulates cellular activities. Second, the studies in question employed different gene-editing models, specifically ST2 transgenic and ST2 knockout models, all of which were based on systemic gene-editing approaches. Consequently, it is essential to carefully consider both the efficiency of gene editing and the tissue-specific characteristics of these models. Developing inducible IL-33/ST2 transgenic or knockout animal models that selectively target specific cell types at defined time points could provide more compelling evidence for the role of IL-33 in wound healing.

Sources of IL-33 during cutaneous wound healing

IL-33 is widely distributed throughout the human tissue. Endothelial cells are one of the main cell sources of IL-33 in the body, and their nuclei are enriched in IL33 protein.²² Endothelial cells often act as important sentinels of immune surveillance to rapidly alert immune cells in case of tissue injury.^23,24 When tissues are injured, endothelial cells rapidly signal to immune cells. Further, in vitro models of endothelial wound healing demonstrate that after endothelial cells fuse into a monolayer, a high nuclear expression of IL-33 can be observed, however, it will be absent when the monolayer is disrupted or when the endothelial cells migrate.²²

Additionally, another significant source of IL-33 protein is epithelial cells, which construct the barrier tissues when exposed to the outside world. Gao et al. observed a significantly higher expression of IL-33 and ST2 in human skin wound specimens within 24 hours post-injury compared to their resting state.²⁵ Furthermore, keratinocytes near the margins of acute human wounds have high expression of IL-33, but not in chronic wounds,¹⁶ indicating a crucial role for IL-33 originated from epithelial cells in wound healing. Notably, the high nuclear expression of IL-33 remains in keratinocytes post-injury, indicating that it may primarily function in transcription regulation rather than as a traditional alarmin.

Important sources of IL-33 during inflammation also include activated fibroblasts, fibroblast-like cells, and myofibroblasts.²⁶ Wulff et al. found that the dermis of mice expressed IL-33 both early and late in wound healing. Using transgenic mice labeled with collagen by green fluorescent protein (GFP), the authors found that fibroblasts expressed IL-33 at 7 days post-injury.²⁷

The ST2expression rapidly increases in the early stages of injury. Gao et al. collected mouse wound tissue at various time points, ranging from 1 hour to 14 days post-injury (0 hours, 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 72 hours, 5 days, 7 days, 10 days, and 14 days after the skin wounds), and found that the peak expression of ST2 occurred at 12 hours and 7 days.²⁵ Wulff et al. revealed the high expression of ST2 in the dermo-epidermal junction of skin near the edge of early wounds, with diminished expression at the wound margin and re-emergence post-reepithelialization. ST2 expression was also observed in the dermis.²⁷

In summary, the primary sources of interleukin-33 (IL-33) following skin trauma are endothelial cells, epidermal cells, and fibroblasts. Consequently, ST2 is highly expressed in wound tissue, likely due to stimulation by IL-33. The binding of IL-33 to the cell surface receptor ST2L transmits signals downstream, thereby regulating the functions of target cells. Mechanisms of IL-33 expression regulation and release

The mechanisms regulating the expression and release of IL-33 appear to be multifaceted, involving both passive and active processes.

Passive release of IL-33

In murine skin, the nuclei of keratinocytes express IL-33 constitutively. After wounding, IL-33 disappears within 6 hours from the nuclei at the wound edges, and necrosis occurs at 24 hours. On the third day post-injury, IL-33 expression intensifies in the thickened multilayers of the epidermis. By the seventh day, when the wound closure is completed, IL-33 expression returns to baseline, suggesting that cellular damage and necrosis can facilitate the passive release of IL-33.²⁸ After mechanical skin damage in mice (via tape stripping), the culture of the damaged skin in vitro revealed a temporary increase in IL-33 levels in the supernatant 1 hour post-injury.²⁹ However, the mechanism by which IL-33 is released extracellularly after injury remains unclear. In vitro, epithelial culture models show that after cellular damage, IL-33FL may be transported into the cytosol in a calcium-dependent manner and subsequently released extracellularly through perforations formed in the cell membrane.^30–32 Enzymes produced by mast cells and neutrophils can process the released IL-33FL into IL-33M, thus significantly enhancing its cytokine activity.^12,33 Both exogenous allergen proteases and endogenous calpains harbor the capability to cleave IL-33.¹³

Active regulation of IL-33

Although IL-33 is constitutively expressed in various cells in a resting state, its expression can be increased or induced when cells are under stress or exposed to inflammatory conditions. Immune stimulants such as TLR ligands, cytokines, and allergens can induce IL-33 expression via the EGFR signaling pathway.^34,35 Studies using the EGFR ligand HB-EGF to stimulate isolated primary human keratinocytes revealed a significant increase in intracellular IL-33FL levels, although it did not promote IL-33 secretion.³⁶ In human keratinocytes, IFN-γ similarly relies on EGFR signaling to induce nuclear IL-33 expression.²⁸ Physical factors like osmotic pressure and mechanical stress can also trigger epithelial cells to produce IL-33.^37–39 Activation of the Notch signaling pathway can induce IL-33nuclear expression in cultured endothelial cells.^40,41

In human skin culture models, normal human skin cultured in growth conditions for 48 hours did not exhibit increased IL-33 expression in the epidermis, but endothelial IL-33 expression was decreased. However, adding IFN-γ to the medium elicited a significant IL-33 expression in keratinocytes of the basal layer within 1 day, demonstrating that inflammatory factors can induce IL-33 expression, which is similar to the observations found in post-trauma models in vivo.²⁸ In contrast, murine keratinocytes do not express IL-33 in vitro or respond sensitively to cytokine activation. Ex vivo cultures of murine skin showed a distribution of IL-33 in the epidermis that matched in vivo findings, but IFN-γ stimulation did not further increase its expression.²⁸ This study highlights significant interspecies variations in the expression and release patterns of IL-33.

Overall, although IL-33 shows a variety of expression and release patterns, its extracellular release appears to be somewhat restricted. Necrotic IL-33FL and histones are co-released during cellular injury, and the presence of the CBM structure prevents IL-33FL from being released rapidly into the extracellular environment. Upon inflammatory stimuli, the human epithelial cells mainly show upregulated IL-33 expression in the nuclei, rather than the cytosol form to secrete to extracellular. Such mechanisms are conducive to maintaining immune homeostasis and preventing excessive inflammation. Kurow et al. created transgenic mice with keratinocytes overexpressing IL-33 of different lengths, and reported that the overexpression of IL-33M (secreted extracellularly) leads to severe inflammatory reactions of the skin, whereas IL-33FL (expressed intracellularly) does not cause spontaneous skin inflammation, underscoring the importance of keeping IL-33 within the producing cell nuclei to avoid undue cytokine activity.⁴²

The role of IL-33/ST2 in target cell function in wound healing

Numerous cell types, such as immune cells, fibroblasts, endothelial cells, and epithelial cells, are involved in the healing process of cutaneous wounds. These cells work collaboratively through the secretion of various cytokines, growth factors, and chemokines to promote the inflammatory, proliferative, and remodeling phases of wound healing, ultimately leading to wound closure. Increasing evidence supports the notion that the inflammatory phase, although described as an early stage of repair, plays a role in nearly every aspect of healing.⁴³ IL-33, a dual-function molecule, exhibits both pro-inflammatory and anti-inflammatory properties.^9,10 Like other members of the IL-1 family, it is released in response to cell injury, activating immune cells and barrier functions to amplify inflammatory responses. Conversely, it also moderates excessive inflammatory responses by inducing type II immune responses, facilitating a shift from pro-inflammatory to reparative healing.^30,33,44 The IL-33/ST2 axis modulates the functions of various immune cells and important cells involved in wound repair (Summarized in Figure 2 and Table 1).

Figure 2.

Sources of IL-33 in Human Skin and Its Role in Wound Healing. Note. IL-33 is mainly distributed in the nuclei of keratinocytes located in the epidermal basal layer, dermal fibroblasts, and endothelial cells in the resting state, which serves as the primary source of IL-33 following skin trauma. Upon skin injury, epidermalIL-33 expression is further elevated by mechanical stress and inflammatory factors, with some IL-33 released extracellularly as cytokines, while the remaining IL-33 retains in the nuclei. After trauma, the increased IL-33 in keratinocytes nuclei promotes epidermal cell proliferation and migration, thus enhancing epithelialization. The nuclear expression of IL-33 is diminished following endothelial cell damage, where extracellular IL-33 then promotes endothelial cell proliferation, migration, and angiogenesis. IL-33 stimulates fibroblasts to synthesize the diverse components of the extracellular matrix. In addition, IL-33 regulates the immune response throughout all stages of wound healing. In the early stages, IL-33 facilitates mast cell degranulation and the secretion of pro-inflammatory factors, and it activates ILC2s to enhance the barrier function of epithelial cells. During the proliferative phase, IL-33 promotes the secretion of pro-healing factors by ILC2s, aids in the differentiation of macrophages from a pro-inflammatory to a pro-proliferative phenotype, and supports the proliferation and migration of Treg cells to inhibit the inflammatory response and facilitate wound healing.

Table 1.

The Function of IL-33 on Target cells/Target tissues in Cutaneous Wound Healing.

Target cell/Tissue	Function	Reference
Keratinocytes	Proliferation/Migration	^16,36
Epithelium	Reepithelialization	¹⁷
Endothelial cells	Inflammatory responses	⁴⁵
Endothelial cells	Migration, Angiogenesis	⁴⁶
Vasculature	Vascular density	²⁰
Fibroblasts	ECM depositon	^17,20,27
Immune cells
Neutrophil	Neutrophilinfiltration	^16,20,47
ILC2	Migration, Type-2 cytokines expression	⁴⁸
ILC2	Increased ILC2 numbers promote reepithelialization	⁴⁹
Mast cell	Proliferation, Inflammatory responses, Cytokine expression	^50,51
Macrophage	Macrophage polarization	^17,20,52,53
Treg	Migration, Inflammation suppression	^54,55

Keratinocytes

Following skin injury, the proliferation and migration of epidermal keratinocytes are crucial for re-epithelialization of the wounds. Keratinocytes initiate complex inflammatory and proliferative responses to maintain the structural and functional integrity of the epidermis. Keratinocytes deficient in IL-33 exhibit reduced migration in vitro scratch assays.¹⁶ Previous sections of this paper have described the increased expression of IL-33 upon EGFR ligands stimulation in human keratinocytes, which benefits the interaction of IL-33 and phosphorylated STAT3 to promote the nuclear translocation and further activation of STAT3, thus providing positive feedback to the HB-EGF/EGFR signaling pathway and facilitating keratinocyte migration. This process does not require the participation of ST2 receptor.³⁶

Endothelial cells

IL-33 affects endothelial cells through the IL-33/ST2 pathway,⁵⁶ where IL-33/ST2 complex promotes angiogenesis and matrix remodeling. The addition of IL-33 to ex vivo cultured endothelial cells enhances the proliferation, migration, and angiogenesis. Furthermore, IL-33 induces angiogenesis in the subcutaneous matrix gel implants in mice via the ST2 receptor.^45,46 Mice with ST2 knockout exhibit a 50% reduction in angiogenesis in granulation tissues of skin wounds, impeding the remodeling process of full-thickness skin injuries.²⁰

Fibroblasts

Dermal fibroblasts express high levels of the ST2. IL-33 directly targets these fibroblasts in vitro, inducing NF-κB activation via ST2 and enhancing collagen expression.²⁷ Conversely, knocking down IL-33 in normal human skin fibroblasts increases the mRNA and protein levels of extracellular matrix genes (COL3A1, COL5A1, and TAGLN),⁵⁷ suggesting that IL-33 exhibits an inhibitory effect on extracellular matrix deposition. These contrasting findings reflect the complex roles of IL-33 in fibroblasts, in which extracellular IL-33 can activate the NF-κB pathway by binding toIL-1RAcP via ST2,¹⁰ while nuclear IL-33 may operate as a transcriptional repressor to reduce and delay NF-κB-triggered gene expression.⁴⁴

Immune cells

Multiple resident immune cells are present in human skin, which form a complex network to monitor tissue damage and participate in wound repair. Nearly all of these immune cells express ST2, through which IL-33 modulates their functions. Strong evidence can be seen in Type 2 immune cells such as Group 2 innate lymphoid cells (ILC2s), mast cells, alternatively activated macrophages (AAMs), and regulatory T cells.^58,59

ILC2s, the innate immune cells critical for barrier tissues, produce cytokines like IL-4, IL-5, and IL-13, which are essential for tissue repair and immune response regulation.⁶⁰ IL-33 activates ILC2s through ST2, leading to the production of IL-13 to promote epithelial cell proliferation and differentiation, thereafter enhancing barrier function.⁴⁸ Exogenous IL-33 treatment promotes epithelialization and wound healing, while IL-33KO mice show diminished ILC2 responses and delayed wound healing. In human skin tissue, ST2 + ILC2- like cells are located at the periphery of dermal wounds, suggesting a role for IL-33 in facilitating cell recruitment, proliferation, or activating ILC2s.⁴⁹

Mast cells (MCs) are often naturally present in the skin and function to degranulate and produce pro-inflammatory cytokines during the inflammatory phase, thus driving the migration of neutrophils and monocytes to inflamed tissues. IL-33 can activate skin mast cells and promote the release of pro-inflammatory cytokines.^50,51 It can also facilitate the release of inflammatory mediators by cross-linking high-affinity IgE receptors.⁶¹ However, the effects of IL-33 on mast cells are bidirectional. For instance, the sensitivity of mast cells to injury varies under acute and chronic exposure conditions . Prolonged exposure to IL-33 significantly reduces the reactivity of mast cells.^61,62,79

Macrophages are pivotal cells involved in injury repair. Depending on their activation state, macrophages can exert various functions.^63,64 Classically activated macrophages dominate the early stages of inflammation, whereas alternatively activated macrophages (AAMs) prevail during the later stages, where they clear dead cells, reduce inflammation, and initiate tissue repair.^65–67 IL-33 stimulates the production of Th2 cytokines (IL-4/IL-13) from cells engaged in type 2 immunity, which in turn stimulate the polarization of macrophages towards an AAM phenotype.^68,69 Moreover, IL-33 can directly promote AAM phenotype polarization, independent of the IL-4 receptor pathway.⁵² In a murine model of muscle injury repair, ST2KO mice showed impaired clearance of damaged muscle cells and defects in resolving inflammation. RNA sequencing confirmed that the IL-33-ST2 axis participates to induce expression of a series of pro-inflammatory and anti-inflammatory genes in macrophages, facilitating their differentiation from a pro-inflammatory to an alternatively activated phenotype.⁵³

Both murine and human skin are replete with regulatory T cells (Tregs) to control inflammation and mediate tissue-specific functions.^34,70 Tregs play a dual role in the process of wound healing. On one hand, Tregs function to suppress the excessive immune response. Tregs migrate and accumulate in the inflammatory sites in the inflammation and tissue remodeling phases. The accumulation of Treg closely correlates with IL-33 expression, for the application of IL-33 signaling pathway inhibitors attenuates Treg accumulation at injury sites, thus exacerbating wound healing.⁵⁴ In addition, a muscle injury model made from mice with specific knockout of the ST2 gene in Treg cells showed reduced accumulation of Tregs and delayed inflammation resolution, which further confirmed the significant impact of the IL-33-ST2 axis on the accumulation,⁵⁵ proliferation, and function of Tregs.⁵⁴ In chemotaxis experiments, IL-33 substantially and dose-dependently induced CD4 + CD25+ Treg cells migration, surpassing the migratory capabilities of known chemokines CCL17, CCL21, and CCL22. On the other hand, Tregs may exert a direct pro-healing function. IL-33 induces Tregs to express amphiregulin, an epidermal growth factor (EGF)-like growth factor that promotes wound healing by activating the EGF receptor (EGFR). Besides, amphiregulin also improves keratinocyte proliferation and migration to contribute to skin injury repair.^34,71

There are also several other types of immune cells resident in the skin, such as dendritic cells, Langerhans cells, T cells, and NK cells. Whether IL-33 also plays a role in wound healing by modulating the functions of these cells have not been sufficiently studied and merits further exploration.

In summary, IL-33 exerts both pro-inflammatory and anti-inflammatory effects at different stages of wound healing. It modulates the functions of immune cells, keratinocytes, endothelial cells, and fibroblasts through multiple mechanisms. Specifically, IL-33 enhances keratinocyte migration, promotes angiogenesis in endothelial cells, and stimulates collagen expression in fibroblasts. Additionally, it influences the responses of immune cells, particularly those associated with type 2 immunity, such as ILC2s, mast cells, macrophages, and regulatory T cells (Tregs). While the role of IL-33 in modulating the functions of other skin-resident immune cells—such as dendritic cells, Langerhans cells, T cells, and natural killer (NK) cells—has not been thoroughly investigated, this area merits further research. Thus, understanding the multifaceted actions of IL-33 in wound healing may yield valuable insights into its therapeutic potential.

The effects of IL33 on chronic wound healing

In numerous pathological conditions, such as diabetes, pressure ulcers, and infectious ulcers, the wound healing process is impeded.⁷² Hyperglycemia in wounds inhibits IL-33expression through glycosylation processes, leading to the reduction of IL-33 proteins. Studies have shown that the application of IL-33 on chronic wounds benefited wound healing. Treating wounds in diabetic mice induced by streptozotocin (STZ) with IL-33 significantly accelerates healing, re-epithelialization, and angiogenesis.^47,73 Furthermore, IL-33 has been used in wounds caused by multiple-resistant staphylococcus aureus (MRSA) infection, where it increases the proliferation of neutrophils and the expression of CXCR2, thus enhancing the early migration of neutrophils to the site of infection to accelerate wound healing.⁷⁴ Wang et al. developed a multifunctional DNA hydrogel wound dressing that encapsulated IL-33 through physical crosslinking to facilitate the sustained release of IL33, the utilization of hydrogel exhibits good biodegradability and antioxidative, immunomodulatory, and anti-inflammatory properties, which the effectively promote the diabetic wounds healing.⁷⁵

Relevant clinical research and therapeutic potential

In the field of clinical research, interleukin-33 (IL-33) has been shown to be elevated in conditions such as acute trauma and central nervous system injuries. Its levels are closely associated with disease prognosis. A study involving 136 patients with severe trauma, primarily due to blunt injuries, continuously monitored the dynamic changes in plasma IL-33 levels following admission. The results indicated a transient and rapid increase in IL-33 levels during the early stages of trauma in patients with severe conditions.⁷⁶ Additionally, Qian et al. conducted a clinical study involving 206 patients with acute ischemic stroke. Their findings revealed the presence of IL-33 in the serum of these patients. Notably, higher serum IL-33 levels were correlated with smaller cerebral infarction volumes and better prognostic outcomes.⁷⁷

However, research on IL-33 in skin wound healing, whether in acute skin injuries or chronic wounds, is relatively limited. This may be due, in part, to the challenges associated with collecting skin samples. In an observational cohort study involving 30 elderly patients with Stage I pressure ulcers, researchers utilized Sebutapes—a non-invasive adhesive tape—to collect inflammatory markers from the sebum in both the ulcerated areas and adjacent healthy skin. The results showed no statistically significant difference in IL-33 levels between the ulcerated and healthy control areas.⁷⁸ This lack of difference may be attributed to the small sample size and the focus on Stage I pressure ulcers, which do not involve open wounds.

Therefore, we proposed that investigating the temporal dynamics of IL-33 expression in peripheral blood and local wound sites in patients with acute and chronic skin injuries, as well as analyzing its correlation with disease severity and prognosis, warrants further research.

Currently, there is also a lack of studies on the application of exogenous IL-33 in clinical skin wound treatment. Given the potential benefits of IL-33 for wound healing observed in animal experiments, exploring exogenous IL-33 as a therapeutic approach to promote chronic wound healing holds significant promise. In this context, identifying the optimal modalities and timing of administration is crucial for its potential translational application in humans. Furthermore, regulating the functions of key cells, such as macrophages and regulatory T cells, by modulating the IL-33 signaling pathway represents a valuable area for future research.

Conclusion

L-33 serves as a multifaceted cytokine, playing a complex and crucial role in skin wound healing. As an alarmin, it rapidly responds to tissue damage and inflammation by activating multiple signaling pathways through its binding with the ST2 receptor and modulating the functions of various cell types, including immune cells, epithelial cells, fibroblasts, and endothelial cells. Additionally, IL-33 participates in the transcriptional regulation within the cell nucleus independently of the ST2 receptor. Besides, it exhibits both pro-inflammatory and anti-inflammatory properties at different stages of wound healing. IL-33 facilitates an appropriate inflammatory response by maintaining immune balance and functioning in the inflammatory, proliferative, and remodeling phases of wound healing. Moreover, IL-33 demonstrates the potential to improve healing processes, particularly in pathological conditions such as diabetes and infectious ulcers. The role of IL-33 in skin wound healing is complex, and further research is necessary to fully elucidate its mechanisms. In the future, IL-33 may become a key target for treating chronic wounds. It may also play a significant role in improving skin healing outcomes.

Footnotes

Acknowledgments

We thank Dr Yuzhou for his invaluable contributions in reviewing the manuscript and assisting with language editing.

Author contribution

Conceptualization and Manuscript drafting: B.L

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is supported by grants from the Natural Science Basic Research Program of Shaanxi Province (2022JM-528).

ORCID iD

Bei Liu

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Interleukin-33 in cutaneous wound healing

Abstract

Keywords

Introduction

Overview of IL-33 and its receptor ST2

IL-33/ST2 in cutaneous wound healing

Transgenic/knockout mice studies

Sources of IL-33 during cutaneous wound healing

Passive release of IL-33

Active regulation of IL-33

The role of IL-33/ST2 in target cell function in wound healing

Keratinocytes

Endothelial cells

Fibroblasts

Immune cells

The effects of IL33 on chronic wound healing

Relevant clinical research and therapeutic potential

Conclusion

Footnotes

Acknowledgments

Author contribution

Declaration of conflicting interests

Funding

ORCID iD

References