Wound healing represents a complex, meticulously orchestrated biological process that requires the coordinated action of multiple cell types, signaling molecules, and extracellular matrix components to restore tissue integrity following injury.
Among the various molecular mediators involved in this process, interleukins—a family of cytokines primarily known for their immunomodulatory functions—have emerged as critical regulators that orchestrate inflammatory responses and repair mechanisms across different tissue types.
The precise regulation of these cytokines determines the balance between beneficial and detrimental inflammation, ultimately influencing healing outcomes in various wound types including oral, dermal, cutaneous, and ocular injuries.
Wound Healing Process and Inflammatory Regulation
Wound healing progresses through three principal phases: the inflammatory phase, which is initiated immediately after injury; the proliferative phase, characterized by the formation of granulation tissue and re-epithelialization; and the remodeling phase, involving matrix reorganization and tissue maturation 1.
The inflammatory phase serves as the foundation for subsequent repair processes, recruiting immune cells that clear debris and pathogens while releasing cytokines and growth factors that coordinate tissue regeneration.
Interleukins function as key modulators of this inflammatory phase, with their precise regulation determining whether inflammation facilitates or impedes the healing process. Research examining wound healing dynamics has demonstrated that proinflammatory cytokines, particularly those in the interleukin family, act as important modulators of the inflammatory process that follows tissue injury 1.
However, the balance between pro-inflammatory and anti-inflammatory cytokines remains critical, as excessive or prolonged inflammation can delay repair processes and contribute to chronic wound development.
Interleukin-1 in Wound Healing: Tissue-Specific Functions
Interleukin-1 (IL-1) has been extensively studied in wound healing contexts, with research revealing intriguing tissue-specific functions for this cytokine. Although IL-1 expression has traditionally been regarded as necessary for healing, its effects have also been implicated in delayed wound repair in certain contexts 1. This apparent contradiction reflects the complex roles IL-1 plays in different tissue environments.
Investigation into IL-1’s function using mice with targeted deletions of IL-1 receptor type 1 (IL-1R1) has revealed that IL-1 signaling plays a critical role in oral wound healing but has minimal effects on dermal wound repair1. After 14 days, wild-type mice exhibited complete closure of intraoral wounds, while IL-1R1-deficient animals showed only partial closure, achieving approximately 50% healing 1.
Furthermore, in IL-1R1-deficient mice, healing tissues displayed a persistent inflammatory cell infiltrate that was absent in wild-type animals, indicating impaired resolution of inflammation 1.
Notably, antibiotic administration significantly reduced the persistent inflammatory infiltrate and improved healing outcomes in IL-1R1-deficient mice, suggesting that IL-1’s principal role in oral wound healing involves protection against bacterial insult rather than direct effects on tissue regeneration 1. This antibacterial protection function appears particularly important in the oral cavity, where wounds are continuously exposed to the diverse microbiome inhabiting this environment.
In sharp contrast to these findings in oral wounds, the rate of healing and recruitment of polymorphonuclear cells in scalp wounds were similar in both IL-1R1-deficient and wild-type mice 1. This differential response highlights the tissue-specific nature of IL-1’s contribution to wound healing, with its importance being more pronounced in environments facing greater microbial challenges.
These findings underscore the concept that IL-1 primarily facilitates the healing process by protecting open wounds from bacterial contamination, particularly in challenging environments like the oral cavity 1.
Interleukin-33 in Cutaneous Wound Healing: Structure and Signaling
Interleukin-33 (IL-33), another member of the IL-1 family, has emerged as a significant regulator of cutaneous wound healing with dual functions as both a nuclear factor and an extracellular cytokine.
The full-length human IL-33 protein (IL-33FL) contains 270 amino acids and consists of three domains: an N-terminal chromatin-binding domain, a central domain, and a C-terminal receptor binding domain 2.
The N-terminal domain includes a highly conserved nuclear localization sequence with a chromatin-binding motif that interacts with histones H2A and H2B, facilitating IL-33 accumulation in the cell nucleus 2.
The C-terminal domain harbors an evolutionarily conserved IL-1-like structure with an essential site for binding to the receptor ST2 2.
IL-33 interacts with its receptor ST2, which exists in two main isoforms: membrane-bound ST2 (ST2L) and soluble ST2 (sST2). While ST2L mediates IL-33 signaling, sST2 functions as a decoy receptor that competes with IL-33 to inhibit signaling pathways 2. This regulatory mechanism provides an additional layer of control over IL-33 activity during wound healing processes.
The central domain of IL-33 contains numerous protease recognition sites that can be cleaved by inflammatory cell proteases, yielding a mature form of IL-33 (IL-33M) with significantly enhanced biological activity—approximately 30-60 times that of full-length IL-33 2.
This proteolytic processing represents an important regulatory mechanism that can amplify IL-33 signaling during inflammatory responses associated with wound healing.
Transgenic and Knockout Studies of IL-33 in Wound Healing
Studies using transgenic and knockout mice have provided valuable insights into the role of the IL-33/ST2 axis in cutaneous wound healing. IL-33 knockout mice demonstrated delayed wound healing with increased neutrophil infiltration and higher levels of inflammatory cytokines compared to wild-type mice, indicating an excessive inflammatory response 2.
Administration of an NF-κB inhibitor to IL-33 knockout mice suppressed the overexpression of inflammatory cytokines like IL-6 and improved healing outcomes, suggesting that nuclear IL-33 promotes wound healing by inhibiting NF-κB activation and reducing pro-inflammatory cytokine production 2.
IL-33 has been shown to promote multiple aspects of the wound healing process, including epithelialization, collagen synthesis, extracellular matrix deposition, and the alternative activation of macrophages toward an anti-inflammatory, pro-healing phenotype 2.
Similarly, studies with ST2 knockout mice revealed impaired wound healing characterized by delayed epithelialization, diminished angiogenesis, and immature collagen components 2.
At four days post-wounding, the wounds of ST2 knockout mice exhibited a higher proportion of pro-inflammatory macrophages and significantly increased neutrophil infiltration 2.
These findings suggest that ST2 receptor signaling facilitates the transition of macrophages from a pro-inflammatory to a repair-promoting phenotype, thereby enhancing epithelialization, angiogenesis, and reducing scar formation 2.
Cellular Sources and Regulation of IL-33 During Wound Healing
Various cell types produce IL-33 during cutaneous wound healing, with expression patterns that change throughout the repair process. Endothelial cells, which function as important immune surveillance sentinels, rapidly alert immune cells following tissue injury 2.
In vitro models of endothelial wound healing demonstrate high nuclear expression of IL-33 when endothelial cells form a monolayer, but this expression disappears when the monolayer is disrupted or when the cells migrate 2. This suggests that IL-33 may play a role in maintaining endothelial barrier integrity under homeostatic conditions.
Keratinocytes near the margins of acute human wounds also display high expression of IL-33, although this expression is notably absent in chronic wounds 2.
The high nuclear expression of IL-33 persists in keratinocytes following injury, indicating that it may function primarily in transcriptional regulation rather than as a traditional alarm in in these cells 2. In the dermis, fibroblasts express IL-33 at both early and late stages of wound healing, with significant expression observed at seven days post-injury 2.
The release of IL-33 occurs through both passive and active mechanisms. Passive release typically follows cellular damage and necrosis, as observed after mechanical skin damage in mice, where IL-33 levels in culture supernatants temporarily increase one hour post-injury 2.
The exact mechanism of IL-33 release remains unclear, but in vitro studies suggest that after cellular damage, full-length IL-33 may be transported into the cytosol in a calcium-dependent manner and subsequently released through perforations in the cell membrane 2.
Once released, enzymes produced by mast cells and neutrophils can process full-length IL-33 into its mature form, significantly enhancing its cytokine activity 2.
Active regulation of IL-33 expression occurs through various signaling pathways.
Stimulation of human keratinocytes with epidermal growth factor receptor (EGFR) ligands like HB-EGF significantly increases intracellular IL-33 levels, although it does not promote IL-33 secretion 2. Similarly, interferon-gamma (IFN-γ) induces nuclear IL-33 expression in human keratinocytes through EGFR signaling 2.
Physical factors such as osmotic pressure and mechanical stress can also trigger IL-33 production in epithelial cells, while activation of the Notch signaling pathway induces nuclear IL-33 expression in cultured endothelial cells 2.
IL-33 Effects on Target Cells in Wound Healing
IL-33 exerts diverse effects on multiple cell types involved in wound healing. In keratinocytes, IL-33 promotes proliferation and migration, contributing to re-epithelialization 2. Keratinocytes deficient in IL-33 show reduced migration in in vitro scratch assays 2.
In human keratinocytes, IL-33 interacts with phosphorylated STAT3 to enhance its nuclear translocation and activation, providing positive feedback to the HB-EGF/EGFR signaling pathway and facilitating keratinocyte migration in a process that does not require ST2 receptor participation 2.
IL-33 also promotes angiogenesis and matrix remodeling by affecting endothelial cells.
The addition of IL-33 to ex vivo cultured endothelial cells enhances their proliferation, migration, and angiogenic capability 2. Furthermore, IL-33 induces angiogenesis in subcutaneous matrix gel implants in mice through the ST2 receptor 2.
Mice lacking the ST2 gene exhibit a 50% reduction in angiogenesis within granulation tissues of skin wounds, impeding the remodeling process of full-thickness skin injuries 2.
IL-33’s effects on fibroblasts appear complex, with seemingly contradictory findings that reflect its dual roles as both a nuclear factor and an extracellular cytokine.
While some studies suggest that IL-33 promotes extracellular matrix deposition, others indicate that knocking down IL-33 in normal human skin fibroblasts increases the expression of extracellular matrix genes, suggesting an inhibitory effect 2.
This complexity arises because extracellular IL-33 can activate the NF-κB pathway by binding to IL-1RAcP via ST2, while nuclear IL-33 may function as a transcriptional repressor that reduces NF-κB-triggered gene expression 2.
IL-33 Regulation of Immune Cells in Wound Healing
IL-33 significantly influences various immune cells involved in wound healing. It activates type 2 innate lymphoid cells (ILC2s) through the ST2 receptor, leading to IL-13 production that promotes epithelial cell proliferation and differentiation, thereby enhancing barrier function 2.
Exogenous IL-33 treatment accelerates epithelialization and wound healing, while IL-33-deficient mice show diminished ILC2 responses and delayed wound healing 2. In human skin tissue, ST2-positive ILC2-like cells localize to the periphery of dermal wounds, suggesting IL-33’s role in cell recruitment, proliferation, or activation 2.
IL-33 exerts bidirectional effects on mast cells, with their sensitivity to injury varying under acute versus chronic exposure conditions 2. Prolonged exposure to IL-33 significantly reduces mast cell reactivity, highlighting the context-dependent nature of IL-33’s immunomodulatory functions 2.
Macrophage polarization represents another important target for IL-33 during wound healing. Classically activated macrophages dominate the early inflammatory phase, while alternatively activated macrophages prevail during later stages when they clear dead cells, reduce inflammation, and initiate tissue repair 2.
IL-33 stimulates the production of Th2 cytokines from cells engaged in type 2 immunity, which in turn promote macrophage polarization toward an alternatively activated phenotype 2. Additionally, IL-33 can directly induce this polarization independent of the IL-4 receptor pathway 2.
In a murine model of muscle injury repair, ST2-deficient mice showed impaired clearance of damaged muscle cells and defects in resolving inflammation, confirming the IL-33-ST2 axis’s role in facilitating macrophage transition from pro-inflammatory to alternatively activated phenotypes 2.
Regulatory T cells (Tregs) also respond to IL-33 during wound healing. Tregs accumulate at injury sites during inflammation and tissue remodeling phases, with their accumulation closely correlating with IL-33 expression 2. IL-33 substantially induces CD4+CD25+ Treg cell migration, surpassing the migratory capabilities of known chemokines 2.
Furthermore, IL-33 stimulates Tregs to express amphiregulin, an epidermal growth factor-like molecule that promotes wound healing by activating EGFR and enhancing keratinocyte proliferation and migration2.
IL-33 in Chronic Wound Healing and Therapeutic Applications
IL-33 shows particular promise for addressing chronic wound healing challenges. In diabetic wounds, hyperglycemia inhibits IL-33 expression through glycosylation processes, leading to reduced IL-33 protein levels 2.
Studies have demonstrated that applying IL-33 to chronic wounds in diabetic mice significantly accelerates healing, re-epithelialization, and angiogenesis 2. IL-33 has also shown efficacy in wounds infected with methicillin-resistant Staphylococcus aureus (MRSA), where it increases neutrophil proliferation and CXCR2 expression, enhancing early neutrophil migration to infection sites and accelerating wound healing2.
Recent technological advances include the development of multifunctional DNA hydrogel wound dressings that encapsulate IL-33 through physical crosslinking for sustained release 2.
These hydrogels demonstrate excellent biodegradability along with antioxidative, immunomodulatory, and anti-inflammatory properties that effectively promote diabetic wound healing 2.
Such innovative delivery systems represent promising approaches for translating IL-33’s beneficial effects into clinical applications for chronic wound management.
Interleukin-11 in Ocular Surface Wound Healing
Interleukin-11 (IL-11), an immunomodulatory cytokine, has recently gained attention for its role in regulating ocular surface inflammation and wound healing. Following corneal injury induced by mechanical removal of the epithelium and anterior stroma, IL-11 levels increase in the cornea, particularly in the stromal layer 3.
Both neutrophils and CD11b+ mononuclear cells (macrophages and monocytes) express substantial levels of the IL-11 receptor, indicating their potential responsiveness to this cytokine 3.
IL-11 exhibits significant anti-inflammatory properties by downregulating immune cell activation. It reduces the expression of major histocompatibility complex class II and tumor necrosis factor-alpha in CD11b+ mononuclear cells while also lowering myeloperoxidase levels in neutrophils 3.
These effects suggest that IL-11 helps control excessive inflammatory responses that might otherwise impede healing processes.
Importantly, topical administration of IL-11 to injured corneas results in faster wound healing and better retention of tissue architecture 3.
These findings demonstrate that IL-11 functions as a key modulator of ocular surface inflammation and provide novel evidence supporting its potential as a therapeutic agent to control inflammatory damage and accelerate wound repair following injury 3.
By dampening excessive inflammation while promoting repair processes, IL-11 creates an optimal environment for wound healing in the ocular surface context.
Comparative Analysis of Interleukins in Different Wound Types
The roles of interleukins in wound healing demonstrate both common features and tissue-specific variations across different anatomical sites. IL-1 plays a critical role in oral wound healing by protecting against bacterial insult but appears less important for dermal wound repair 1.
This tissue-specific function likely reflects the distinct microenvironments of these sites, with the oral cavity presenting greater bacterial challenges than typically encountered in dermal wounds.
In contrast, IL-33 exhibits broad functionality in cutaneous wound healing, influencing multiple cell types involved in tissue repair 2. Its dual roles as both a nuclear factor and an extracellular cytokine allow it to regulate gene expression directly while also modulating immune cell functions through receptor-mediated signaling.
The prominence of IL-33 in both early and late stages of wound healing highlights its versatility in coordinating different aspects of the repair process.
IL-11 appears to function primarily as an anti-inflammatory mediator in ocular surface wounds, creating conditions conducive to accelerated healing by preventing excessive inflammation3. This immunomodulatory role resembles certain aspects of IL-33 function but with tissue-specific manifestations in the corneal environment.
These varied roles underscore the importance of context in determining interleukin function during wound healing. Factors such as bacterial load, tissue vascularization, mechanical stress, and resident immune cell populations all influence how interleukins shape the wound healing response in different anatomical locations.
Therapeutic Implications and Future Directions
The understanding of how different interleukins regulate wound healing processes offers promising avenues for therapeutic interventions. For IL-1, targeted approaches might be particularly beneficial in oral wounds, where bacterial contamination presents significant challenges to healing 1.
Modulating IL-1 signaling could help balance its protective effects against pathogens while preventing excessive inflammation that might delay healing.
IL-33 presents multiple therapeutic possibilities for cutaneous wounds, especially in chronic settings like diabetic ulcers where its expression is naturally reduced 2. Exogenous IL-33 application has shown promise in accelerating diabetic wound healing and combating MRSA infections 2.
Novel delivery systems, including DNA hydrogel wound dressings that provide sustained IL-33 release, represent significant advances that could translate to improved clinical outcomes 2.
IL-11’s anti-inflammatory properties make it an attractive candidate for treating ocular surface injuries 3. Its ability to downregulate immune cell activation while promoting tissue repair suggests potential applications for conditions where excessive inflammation impedes corneal healing, such as severe dry eye disease or chemical injuries.
Future research directions should focus on developing precision medicine approaches that tailor interleukin-based therapies to specific wound types and patient characteristics.
Understanding the interplay between different interleukins and other wound healing mediators will be essential for designing combination therapies that address multiple aspects of impaired healing simultaneously.
Conclusion
Interleukins play diverse and critical roles in wound healing across different tissue environments. IL-1 facilitates oral wound healing primarily through protection against bacterial insult, with minimal effects on dermal wound repair.
IL-33 orchestrates multiple aspects of cutaneous wound healing by influencing keratinocytes, endothelial cells, fibroblasts, and various immune cells, promoting epithelialization, angiogenesis, and balanced inflammatory responses.
IL-11 modulates ocular surface inflammation, creating conditions that accelerate wound healing while preserving tissue architecture.
The tissue-specific functions of these interleukins highlight the complexity of wound healing regulation and the importance of context in determining cytokine effects.
Understanding these nuanced roles provides opportunities for developing targeted therapeutic approaches that address specific aspects of impaired healing.
As research continues to elucidate the molecular mechanisms through which interleukins influence wound healing, new therapeutic strategies will likely emerge with the potential to transform wound management, particularly for challenging conditions like chronic wounds, infected wounds, and wounds in immunocompromised individuals.
The continued investigation of interleukin functions in wound healing not only advances our fundamental understanding of tissue repair processes but also creates pathways toward innovative clinical interventions that harness these powerful immunomodulatory molecules to promote optimal healing outcomes across diverse tissue types and pathological conditions.