The IL-4/IL-13 Axis in Skin Fibrosis and Scarring: Mechanistic Concepts and Therapeutic Targets

Abstract

Background:

Skin fibrosis, characterized by excessive fibroblast proliferation and extracellular matrix deposition in the dermis, is the histopathologic hallmark of dermatologic diseases such as systemic sclerosis, hypertrophic scars, and keloids. Effective anti-scarring therapeutics remain an unmet need, underscoring the complex pathophysiologic mechanisms of skin fibrosis. The Th2 cytokines interleukin (IL)-4 and IL-13 have been implicated as key mediators in the pathogenesis of fibroproliferative disorders.

Objective:

To summarize the current understanding of the role of the IL-4/IL-13 axis in wound healing and skin fibrosis.

Methods:

A literature search identified research studies investigating the roles of IL-4 and IL-13 in fibrotic skin diseases.

Results:

While transforming growth factor-beta has long been regarded as the main driver of fibrotic processes, research into the cellular and molecular biology of wound healing has revealed other pathways that promote scar tissue formation. IL-4 and IL-13 are important mediators of skin fibrosis, supported by evidence from in vitro data, animal models of fibrosis, and clinical studies. Overactive signaling of the IL-4/IL-13 axis contributes to the initiation and perpetuation of fibrotic skin diseases.

Conclusion:

Further insights into the IL-4/IL-13 axis may reveal potential targets for the development of novel therapies that prevent or treat fibrotic skin diseases.

Introduction

Tissue fibrosis is a leading cause of morbidity and mortality worldwide, with an estimated 45% of all deaths in the United States being attributed to fibroproliferative disorders (FPDs) [36, 145]. Fibrosis represents an exaggerated wound healing response following tissue damage, which may be triggered by a variety of stimuli such as infection, autoimmune reaction, and mechanical injury [143, 147]. Characterized by excessive fibroblast proliferation and collagen-rich extracellular matrix (ECM) deposition, fibrosis can affect any organ, leading to permanent scarring and impaired organ function [143]. Skin fibrosis is the histopathologic hallmark of a wide spectrum of dermatologic diseases, including systemic sclerosis (SSc; scleroderma), chronic graft-versus-host disease (GVHD), nephrogenic fibrosing dermopathy, scleromyxedema, and restrictive dermopathy [76, 134]. Localized skin fibrosis can also develop as a sequela of dermal injury (e.g., burns, surgery, trauma, infection, radiation), manifested clinically as hypertrophic scars or keloids [66, 130].

Skin fibrosis is a significant global health problem affecting over 100 million persons per year in the developed world [8, 17]. Cutaneous scars have a profoundly negative impact on patients’ quality of life due to associated pain and pruritus, functional impairment, cosmetic disfigurement, and psychosocial distress [8, 11, 15]. There is no universal consensus on optimal scar management despite high demand for modalities that prevent, reduce, or remove scars, as evidenced by an estimated $12 billion annual market for scar treatment in the US [121, 130]. Current anti-scarring therapeutics have limited clinical efficacy and varying levels of research evidence to support their use, making scar treatment a major unmet need [38, 133]. While significant advances have been made in our understanding of wound healing biology, the exact pathophysiologic mechanisms underlying fibrosis remain unclear.

Research on cutaneous scarring has focused on identifying new therapeutic targets, such as profibrotic cytokines, to develop novel pharmacologic agents that may facilitate optimal or scarless wound healing [42, 79, 136]. Cytokines are signaling molecules of the immune system that regulate fundamental biological processes such as host defense, inflammation, cell growth, angiogenesis, and tissue repair [103]. The T-helper type 2 (Th2) cytokines interleukin (IL)-4 and IL-13 have been implicated in the pathogenesis of FPDs such as pulmonary fibrosis, cirrhosis, myocardial fibrosis, progressive kidney disease, pathological cutaneous scars, and SSc [36, 143].

SSc is an autoimmune connective tissue disorder characterized by chronic inflammation, small vessel vasculopathy, and progressive fibrosis of the skin and internal organs [97]. Since FPDs share common pathomechanistic pathways, SSc is often used as the prototypical fibrotic disease to study the cellular and molecular mechanisms underlying fibrosis [1, 135]. The most thoroughly investigated animal model of fibrosis is the spontaneously occurring tight-skin (TSK/+) mutant mouse, which exhibits a SSc-like syndrome with clinical features including diffuse cutaneous hyperplasia, myocardial hypertrophy, and pulmonary emphysema [10, 26]. The TSK/+ mouse model has been instrumental in revealing the profibrotic effects of IL-4 and IL-13, and will be referred to throughout this review [76].

Herein, we discuss how dysregulated wound healing and Th2-associated immune responses contribute to the pathogenesis of fibrosis. We then review the biological characteristics of IL-4 and IL-13, their signaling pathways, and their pathogenic roles in skin fibrosis as elucidated by laboratory and clinical investigations. This review article serves to highlight the current evidence and therapeutic potential of targeting the IL-4/IL-13 axis for skin fibrosis, as novel biologic agents that inhibit IL-4/IL-13 and their downstream mediators have been recently approved or are currently under development with promising results for the treatment of various allergic and immunologic diseases [57, 115].

Cutaneous Wound Healing

Wound healing is a complex and dynamic process that involves highly regulated pathways to restore tissue architecture and function after injury. Physiologic cutaneous wound healing is characterized by three distinct yet overlapping phases: inflammation (immediate to 1–3 days), proliferation (4 days to 3 weeks), and remodeling (3 weeks to over a year) [42, 105].

The inflammatory phase aims to contain the injury, form a fibrin hemostatic plug, remove tissue debris, and prevent infection [105]. The proliferative phase is characterized by the migration of reparative cells into the provisional wound matrix, angiogenesis, re-epithelialization, formation of granulation tissue, and progressive restoration of tissue function [61, 62]. The predominant cells in granulation tissue are fibroblasts, which produce ECM proteins such as type I collagen, type III collagen, and fibronectin, forming a structural framework for cell adhesion and differentiation [105, 125]. In response to growth factors and cytokines, fibroblasts proliferate and transform into myofibroblasts, which express alpha smooth actin (α-SMA) and are key players of normal tissue repair and fibrosis [25, 143]. Compared to fibroblasts, myofibroblasts have increased activity of ECM biosynthesis and enhanced contractility to induce wound closure [24, 149]. During the remodeling phase, the ECM is reorganized to provide more strength and elasticity to connective tissue, the orientation of collagen fibrils becomes more uniform, and the tensile strength of the wound increases [10, 79].

Normally, the ECM is in a constant flux of remodeling by resident quiescent fibroblasts, whereby synthesis and degradation of ECM components are closely regulated to maintain a homeostatic balance [10, 147]. The perturbation of any wound healing phase can shift this balance to a pathological state of “over repair” or “over healing,” characterized by excessive collagen deposition and failure to restore tissue function, resulting in fibrosis [42, 147]. While scar tissue formation is an expected outcome of wound healing after skin injury, it can range from minimally visible scarring to severe thickening and tightening of the skin [55]. In fibrosis, myofibroblasts drive excessive collagen production in a dysregulated manner and resist the induction of apoptosis [76]. Therefore, it is important to understand the cytokine networks that influence fibroblast activity in normal and pathological wound healing.

Type 2 Immunity and Fibrosis

The immune system plays an essential regulatory role in balancing wound repair and tissue regeneration following insults such as infection and mechanical injury [62, 144]. Type 1 (Th1-mediated) and type 2 (Th2-mediated) immune responses involve opposing effector functions and are each characterized by a distinct repertoire of cytokines (Figure 1) [75]. Pro-inflammatory Th1 cytokines (interferon-gamma, tumor necrosis factor-beta, IL-2 and IL-12) drive cellular immunity and phagocyte-dependent inflammation, which are critical for host defense against intracellular pathogens [36, 103]. In contrast, anti-inflammatory Th2 cytokines (IL-4, IL-5, IL-9, IL-10, and IL-13) evoke strong humoral responses and promote barrier defenses, involved in protection against extracellular parasites [2, 36]. The type 2 immune response is classically viewed as a counterbalance for the tissue damage and inflammation caused by type 1 immunity [34, 73].

Figure 1.

Type 1 immunity, characterized by pro-inflammatory Th1 cytokines, promotes tissue-damaging inflammation as a defense against intracellular pathogens. Type 2 immunity, characterized by anti-inflammatory Th2 cytokines, helps to counter Th1-mediated inflammation and regulates tissue repair following injury. Normally, type 1 and type 2 immune responses are tightly regulated to maintain homeostasis. Over-activation of either immune response may lead to various disease states. For example, disproportionately increased activity of the Th2 cytokines IL-4 and IL-13 contributes to the pathogenesis of fibroproliferative disorders. IFN-γ, interferon-gamma; IL, interleukin; TNF-β, tumor necrosis factor-beta

In addition to suppressing type 1-driven inflammation, type 2 immunity is closely involved in many aspects of wound healing through the production of mediators that facilitate tissue repair and regeneration [2, 34, 36]. Th2 cytokines upregulate genes known to be involved in the mechanisms of wound healing and fibrosis [51]. When Th2 cytokine responses become overactive, chronic, or dysregulated, they may drive overzealous repair mechanisms that trigger disease states such as allergy and fibrosis (Figure 1) [34, 36, 131, 144]. Specifically, IL-4 and IL-13 have been identified as potent mediators that are critical to the induction and perpetuation of atopic diseases and FPDs [33, 144].

IL-4 and IL-13 in Skin Fibrosis and Scarring

IL-4 and IL-13 have similar and distinct biological characteristics

The IL-4/IL-13 axis has been studied extensively as a potential therapeutic target in Th2-driven diseases such as asthma, atopic dermatitis, and cancer [80, 144]. More recently, IL-4 and IL-13 have gained attention for their important roles in tissue repair and fibrosis. Persistent activation of IL-4 and IL-13 signaling leads to abnormal collagen homeostasis and has been implicated in the pathogenesis of FPDs [36, 100, 145].

IL-4 and IL-13 are short α-helix bundle secreted glycoproteins with approximately 30% homology, encoded by a cytokine gene cluster on chromosome 5q [10, 82]. They are mainly produced by Th2-polarized T cells but are also secreted by natural killer T cells, activated mast cells, eosinophils, basophils, macrophages, and dendritic cells [40, 53]. IL-4 and IL-13 elicit many similar biological responses since they share a common receptor chain, IL-4 receptor alpha (IL-4Rα), and the Janus kinase/signal transducer and activator of transcription protein 6 (JAK/STAT6) signaling pathway [145]. In cutaneous wound healing, IL-4 and IL-13 promote fibroblast chemotaxis and proliferation, myofibroblast differentiation, and production of collagen and ECM macromolecules [14, 118, 145]. Although IL-4 and IL-13 share many effector functions, mechanistic studies conducted with knockout mice and neutralizing antibodies have revealed their distinct and non-redundant roles in the regulation of tissue repair [21, 143, 146].

IL-4 and IL-13 activate the IL-4Rα/STAT6 pathway to promote fibrosis

IL-4 and IL-13 can influence almost all cell types as their surface receptors are widely expressed [82, 141]. IL-4 and IL-13 signal through receptor heterodimers composed of three possible subunits: IL-4Rα, the common gamma chain (γc), and IL-13Rα1 (Figure 2) [40, 82]. IL-4 and IL-13 both share the type I receptor complex composed of IL-4Rα and γc. IL-4 also binds to the type II receptor composed of IL-4Rα and IL-13Rα1. IL-13 binds with much higher affinity to the IL-13Rα2 subunit, which is traditionally considered a “decoy” receptor as it has a short cytoplasmic tail with no recognizable signaling motifs [16, 20]. However, Fichtner-Feigl et al. found that IL-13 can activate IL-13Rα2 to induce transforming growth factor-beta (TGF-β) production and ultimately fibrosis [29, 77].

Figure 2.

IL-4 and IL-13 share the type I receptor complex composed of the IL-4Rα chain and the common gamma chain (γc). IL-4 also binds to the type II receptor complex composed of IL-4Rα and the IL-13Rα1 chain. IL-13 binds with high affinity to the IL-13Rα2 subunit that is traditionally considered a “decoy” monomeric receptor, but has been shown to participate in signal transduction.

The binding of IL-4 and IL-13 to their cognate receptors results in JAK activation, with type I receptors activating JAK1/JAK3 and type II receptors activating JAK1 and TYK2/JAK2 [53]. Activated JAKs initiate several intracellular signaling cascades by phosphorylating specific tyrosine residues in the cytoplasmic domain of the IL-4Rα subunit [21, 82]. The phosphorylated tyrosine residues act as docking sites for signaling molecules such as STAT6, which forms homodimers and translocates to the nucleus, activating IL-4- and IL-13-responsive genes (Figure 3) [21, 82]. In the context of fibrosis, IL-4 and IL-13 upregulate the promoter activity and transcription of profibrotic genes such as type I collagen and TGF-β, the prototypical profibrotic cytokine [10, 58]. Thus, overactivity of IL-4 and IL-13 leads to stimulation of profibrotic pathways that drive excessive fibroblast proliferation and ECM deposition.

Figure 3.

IL-4 and IL-13 binding to their cognate cell surface receptors activates the cytoplasmic domain of IL-4Rα and associated JAK1, creating docking sites for signaling molecules such as STAT6. Phosphorylated STAT6 monomers form homodimers and translocate to the nucleus, leading to the activation of target genes involved in fibrosis.

The IL-4Rα/STAT6 signaling pathway has been investigated as a potential therapeutic target to block the progression of FPDs [71, 139]. Alternatively activated (M2) macrophages induced by IL-4Rα signaling has been proposed as a means by which IL-4 and IL-13 mediate skin fibrosis [145, 147]. IL-4Rα-dependent M2 macrophages are found in abundance during chronic Th2 cytokine responses, and during skin repair, they direct wound resolution via collagen fibril assembly and cross-linking [59, 74, 148]. Prolonged infiltration of M2 macrophages has been observed in hypertrophic scars, and the depletion of these macrophages during the subacute phase of wound healing allows normal scarring in mice with human skin transplants [62, 149]. In injured mouse skin, the IL-4Rα signaling pathway is critical for effective wound repair, and overstimulation of IL-4Rα can result in exuberant scar formation [59]. In addition, intact IL-4Rα signaling is required to induce a rapid elevation of proteins associated with Th2-mediated tissue repair in a surgical mouse model [2, 74]. IL-4Rα is more highly expressed in TSK/+ murine fibroblasts and SSc dermal fibroblasts compared with normal controls, resulting in stronger activation of STAT6 upon cytokine stimulation and correlating with increased collagen gene activity [84, 85]. Targeted deletion of the IL-4Rα gene in TSK/+ mice ameliorates the key fibrotic characteristics of the TSK syndrome including dermal thickening, further supporting IL-4Rα’s critical role in the pathogenesis of skin fibrosis [83].

IL-4 and IL-13 exert profibrotic effects through TGF-β, a central mediator of fibrosis

There is strong evidence to suggest that the profibrotic activities of IL-4 and IL-13 are mediated in great extent by TGF-β, a potent profibrotic cytokine and key driver of ECM formation and tissue remodeling [10, 65, 143, 145, 146]. TGF-β is consistently overexpressed in virtually all fibrotic diseases, with production levels correlating with the progression of fibrosis [76, 138, 147]. IL-4 and IL-13 may act through TGF-β to trigger fibrosis by directly activating TGF-β production or stimulating pathways promote TGF-β signaling [143, 147]. The canonical SMAD signaling pathway plays a crucial role in governing TGF-β-induced fibrosis, with downstream targets including connective tissue growth factor, α-SMA, collagens, and matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) (Figure 4) [49, 64, 87]. Tissue fibrosis is reduced in Smad3-deficient mice, confirming the importance of the TGF-β/SMAD pathway in certain fibrotic processes [143]. The profibrotic effects of TGF-β include the stimulation of fibroblast chemotaxis, differentiation, proliferation, and ECM synthesis and deposition [14, 72]. TGF-β also acts through Smad-independent signal transduction pathways to promote fibrosis, the mechanisms of which are covered in other reviews [49, 64].

Figure 4.

The profibrotic actions of TGF-β are positively regulated by Th2 cytokines IL-4 and IL-13. TGB-β can induce fibrosis via the canonical SMAD signaling pathway. The binding of TGF-β ligands to their cognate receptors activates a cascade of SMAD proteins, which form a complex and translocate to the nucleus to transcribe specific genes. The expression of fibrosis-associated genes, such as collagen and fibronectin, results in ECM deposition, fibroblast proliferation, and myofibroblast differentiation. While these biological processes constitute physiologic wound healing, overactive TGF-β/SMAD signaling can lead to tissue fibrosis.

α-SMA, alpha smooth muscle actin; CTGF, connective tissue growth factor; ECM, extracellular matrix; MMPs, matrix metalloproteinases; TGF-β, transforming growth factor-beta; TIMPs, tissue inhibitors of metalloproteinases

Fibroblasts isolated from hypertrophic scars and keloids overexpress proteins involved in TGF-β signal transduction, and hypertrophic scar fibroblasts have been shown to produce approximately twice as much TGF-β1 as do normal skin fibroblasts [103, 105]. Blockade of TGF-β signaling has been shown to reduce ECM deposition and improve scar appearance in rat wounds, prevent the overexpression of collagen genes in SSc fibroblasts, and prevent skin fibrosis in a sclerodermatous GVHD mouse model [54, 81, 122, 123].

IL-4 is a potent mediator of skin fibrosis and scarring

Several studies have shown that IL-4 is a major profibrotic cytokine that stimulates collagen synthesis by fibroblasts. In response to IL-4 in vitro, human dermal fibroblasts synthesize a dose-dependent increase in pre-collagen mRNAs, resulting in elevated levels of types I and III collagen and fibronectin [37, 104]. This stimulatory effect is neutralized specifically by anti-IL-4 antibodies [104]. Significantly higher levels of IL-4 are detected in skin biopsy specimens, dermal fibroblast cultures, and sera of SSc patients compared to controls [47, 90, 117]. Similar stimulatory effects of IL-4 on collagen synthesis have been observed in human dermal fibroblasts isolated from SSc patients and normal counterparts, as well as in normal and TSK/+ murine fibroblasts [28, 83, 117]. TSK/+ fibroblasts are hyperresponsive to IL-4, displaying increased collagen promoter region activity, collagen gene transcription, and type I collagen protein synthesis compared to controls [84]. IL-4 was also found to promote biosynthesis of collagen proteins by increased stability and transcription of the collagen mRNA in SSc fibroblasts in culture [67].

Significant positive correlations between IL-4 activity and fibrosis have also been demonstrated in animal models. Salmon-Ehr et al. showed that IL-4 is strongly expressed during the early phases of normal wound healing in mouse skin and decreases after wound closure [118]. Topical application of exogenous IL-4 on acute cutaneous wounds in mice induces a significant increase in the formation of fibrotic tissue, whereas the administration of IL-4 antisense oligonucleotides significantly delays wound healing [118]. These results implicate IL-4 production in normal wound healing. Overexpression of IL-4 in transgenic mice results in fibroblast proliferation and increased focal deposition of collagen in the dermis [27]. Conversely, inhibition of IL-4 responses via administration of anti-IL-4 monoclonal antibodies reduces dermal collagen deposition, preventing progression of cutaneous fibrosis in murine models of SSc and chronic skin allograft rejection [88, 99].

The central role of IL-4 in skin fibrosis has also been demonstrated by knockout mouse studies. Neutralizing anti-IL-4 antibodies given to young TSK/+ mice normalizes dermal collagen content and prevents dermal fibrosis [99]. Furthermore, the development of skin fibrosis is completely abrogated in TSK/+ mice with null mutation of either the IL-4 or Stat6 genes [98]. McGaha et al. demonstrated that targeted deletion of the IL-4Rα gene in TSK/+ mice prevents the development of dermal thickening and lowers the level of dermal hydroxyproline content to be similar to that of control mice, highlighting the importance of IL-4 for the development of cutaneous fibrosis [83]. Interestingly, disruption of the IL-4 gene not only rescues mice with the embryonic lethal homozygous TSK/TSK mutation from death, but also prevents the hallmark cutaneous hyperplasia of the TSK syndrome and substantially decreases TGF-β production by fibroblasts in vitro [60].

Altogether, these data show that IL-4 is a key profibrotic agent with important roles in mediating ECM synthesis to maintain tissue integrity. While IL-4 promotes collagen production to maintain normal physiologic processes, its dysregulation can result in abnormal wound healing and fibrotic disease.

IL-13 is a potent mediator of skin fibrosis and scarring

As part of physiologic wound healing, IL-13 directly activates fibroblast proliferation and differentiation, and also induces gene expression of type I collagen and other critical fibrosis-associated proteins such as α-SMA, the hallmark of myofibroblasts [53]. IL-13 has been shown to upregulate total collagen generation in fibroblasts of normal human skin and keloids, with a more rapid and greater magnitude of collagen response to IL-13 stimulation observed in keloid-derived fibroblasts [100]. A study using cDNA microarray analysis to identify IL-13 target genes showed that IL-13 mediates the transcriptional activation of the α2(I) collagen gene in human dermal fibroblasts in a dose-dependent manner [56]. The STAT6 signaling pathway was essential for this induction, as the addition of STAT6 antisense nucleotide resulted in a near complete inhibition of IL-13 effect on α2(I) collagen gene and type I collagen protein expression [56]. Furthermore, IL-13 specifically induces the gene expression of procollagen 3α1, which has been described as an early marker of active fibrosis and a poor clinical prognostic indicator in FPDs [100]. In addition to stimulating dermal collagen deposition, IL-13 also exerts profibrotic effects by hindering collagen degradation through inhibition of MMPs and upregulation of TIMPs in fibroblasts [100]. MMPs are zinc-dependent proteinases that cleave collagen and other ECM components, whereas TIMPs block the activity of MMPs [150]. Therefore, IL-13 has pleiotropic effects on fibrotic processes.

IL-13 has been identified as the dominant effector cytokine of fibrosis in several FPD models [14, 145]. Serum levels of IL-13 are significantly elevated in patients with SSc and localized scleroderma compared with healthy controls, and these levels positively correlate with the extent of skin fibrosis and levels of inflammatory biomarkers [32, 47, 48]. Furthermore, IL-13-producing circulating CD8+ T cells isolated from SSc patients express skin-homing receptors and induce a profibrotic phenotype in normal dermal fibroblasts in vitro, which is inhibited by anti-IL-13 antibody [30, 31]. Interestingly, in the sclerodermatous GVHD murine model, genetic deficiency of either IL-13 or IL-4Rα conferred complete protection from fibrotic disease based on histological and clinical evidence, suggesting that IL-13 signaling is essential in this model of fibrosis [41].

The factors that regulate IL-13 expression in fibrotic disease remain incompletely understood. However, emerging evidence implicates IL-33 as an upstream inducer of IL-13 in the immune system [41]. IL-33 is constitutively expressed in the skin and its increased expression in activated dermal fibroblasts is correlated with skin fibrotic disorders [109]. Subcutaneous injection of IL-33 in mice is sufficient to drive the development of cutaneous fibrosis, with skin samples showing significantly elevated expression of IL-4 and IL-13 [109]. This response is attenuated IL-13 knockout mice [109]. In SSc patients, higher circulating levels of IL-33 correlate with the extent of skin fibrosis and microvascular damage [97].

Altogether, the research studies discussed in this review support the crucial roles of Th2 cytokines in regulating tissue remodeling and ECM homeostasis. While IL-4 and IL-13 exert important wound healing mechanisms in response to tissue damage or type 1 immune-mediated inflammation, their dysregulation can lead to overzealous tissue repair and ultimately fibrotic disease.

Future Directions

There is a large unmet need for innovative therapeutic strategies to prevent and treat skin fibrosis and pathological scars [89]. Despite the substantial societal and economic burden of skin fibrosis, there is no “gold standard” for scar management and current treatments have limited clinical efficacy [39, 133]. The translation of research evidence into clinical practice and therapeutic applications has lagged, underscoring the complexity of fibrotic disease mechanisms.

Understanding the regulation and mechanisms of cytokine action has led to the development of new treatments that have the promise of slowing the progression of disease and potentially altering the natural history of disease. Based on observations in animal models of fibrosis, pathologic scar formation may be mitigated via targeted modulation of profibrotic cytokine responses. Therefore, therapies that inhibit the IL-4/IL-13 axis may be a potential strategy to limit skin fibrosis.

While murine studies have provided significant insights into the pathogenesis of cutaneous scarring, there is no ideal model that accurately recapitulates all human features of dermal fibrosis [4, 9]. As such, the translation of findings from preclinical experiments into therapeutics that attenuate the fibrotic response in humans may not be linear.

Biologic agents targeted against IL-4 and/or IL-13 are already approved or under clinical investigation for therapeutic use in various Th2-driven diseases (Table 1) [7, 63, 78, 80, 129, 137]. Dupilumab, a fully humanized monoclonal antibody against IL-4Rα, is currently the only approved biologic that targets the IL-4/IL-13 axis and is approved for use in the treatment of atopic dermatitis and asthma [112, 124]. In addition, there are two biologic agents (SAR156597 and QBX258) in clinical development that bind and neutralize both IL-4 and IL-13, thereby preventing signaling effects of the entire IL-4/IL-13 axis [68]. Ongoing clinical trials are assessing the efficacy of SAR156597 and QBX258 in treating diffuse cutaneous SSc and lymphedema, respectively [86, 119]. Since FPDs share common mechanistic pathways, these drugs may potentially be repurposed for the treatment of fibrotic skin diseases.

Table 1.

Summary of biologic agents that target the IL-4/IL-13 axis for the treatment of Th2-driven diseases

Target	Drug name (alternative)	Developers	Molecule	Condition	Developmental status
IL-4	Altrakincept (Nuvance)	Amgen	Recombinant human soluble IL-4Rα	Asthma	Halted after Phase III [13, 129]
	Pascolizumab (SB 240683)	GlaxoSmithKline	Humanized mAb	Asthma	Terminated in Phase I/II [46, 78]
	VAK694	Novartis	Human mAb	AR	Completed Phase II [19]
IL-4Rα	AIR-645	Altair Therapeutics	Antisense IL-4Rα	Asthma	Completed Phase II [3, 18]
	AMG-317	Amgen	Human mAb	Asthma	Completed Phase II [22, 80]
	Dupilumab (Dupixent)	Regeneron; Sanofi	Human mAb	AD AR Asthma EoE Nasal polyposis	FDA approved [124, 126] Undergoing Phase II [110] FDA approved [107] Undergoing Phase III [111] Completed Phase III [6, 120]
	MEDI 9314	AstraZeneca	Human mAb	AD	Halted after Phase I [5, 63]
	Pitrakinra (Aerovant, Aeroderm)	Aerovance	Recombinant human protein of IL-4 mutein	Asthma AD	Completed Phase II [140] Completed Phase II [80]
IL-13	Anrukinzuma b (IMA-638)	Wyeth (Pfizer)	Humanized mAb	Asthma UC	Halted after Phase II [35, 106] Halted after Phase II [52, 113]
	Dectrekumab (QAX576)	Novartis	Human mAb	AR Asthma CD EoE IPF Keloids PF due to SSc	Completed Phase II [91] Halted after Phase II [68] Completed Phase II [92] Completed Phase II [116] Terminated in Phase II [93] Terminated in Phase II [94] Terminated in Phase II [95, 97]
	GSK679586	GlaxoSmithKline	Humanized mAb	Asthma	Completed Phase II [12]
	IMA-026	Wyeth (Pfizer)	Humanized mAb	Asthma	Completed Phase I/II [35]
	Lebrikizumab	Roche; Dermira	Humanized mAb	AD Asthma IPF	Completed Phase II [127] Completed III [44, 45] Completed Phase II [128]
	Tralokinumab (CAT-354)	MedImmune (AstraZeneca); LEO Pharma	Human mAb	AD Alopecia areata Asthma IPF UC	Undergoing Phase III [69, 70, 142] Completed Phase II [43, 114] Completed Phase III [101] Terminated in Phase II [102] Completed Phase II [23]
	RPC4046 (ABT-308)	AbbVie; Receptos (Celgene)	Humanized mAb	Asthma EoE	Completed Phase I [132] Completed Phase II [50]
IL-4 and IL-13	QBX258 (VAK694 + dectrekumab)	Novartis	Combination of two human mAbs	Asthma BCRL	Completed Phase II [96] Completed pilot study [86]
	SAR156597 (ACT14604)	Sanofi	Humanized bispecific mAb	IPF Skin fibrosis in SSc	Completed Phase II [108] Undergoing Phase II [119]

AD, atopic dermatitis; AR, allergic rhinitis; BCRL, breast cancer related lymphedema; CD, Crohn’s disease; EoE, eosinophilic esophagitis; FDA, Food and Drug Administration; IL, interleukin; IL-4Rα, interleukin-4 receptor α-subunit; IPF, idiopathic pulmonary fibrosis; mAb, monoclonal antibody; PF, pulmonary fibrosis; SSc, systemic sclerosis; UC, ulcerative colitis

Conclusions

Skin fibrosis is the result of an exaggerated wound healing response and underlies the pathogenesis of a wide spectrum of cutaneous diseases such as SSc and pathologic cutaneous scars. Despite the socioeconomic burden of skin fibrosis, effective and durable scar treatment remains a significant unmet need in clinical medicine. Research on cellular and molecular wound healing biology has revealed key molecular players that may be targeted for pharmacologic intervention in the treatment of fibrosis. IL-4 and IL-13 are immunoregulatory Th2 cytokines that mediate important profibrotic effects, including fibroblast proliferation and collagen synthesis. Biologic agents that target the IL-4/IL-13 axis may provide a promising therapeutic modality for patients with skin fibrosis and are worthy of further investigation.