Abstract
Chronic wounds exhibit persistent inflammation with markedly delayed healing. The significant burden of chronic wounds, which are often resistant to standard therapy, prompts further research on novel therapies. Since the interleukin-17 family has been implicated as a group of proinflammatory cytokines in immune-mediated diseases in the gut and connective tissue, as well as inflammatory skin conditions, we consider here if it may contribute to the pathogenesis of chronic wounds. In this review, we discuss the interleukin-17 family's signaling pathways and role in tissue repair. A PubMed review of the English literature on interleukin-17, wound healing, chronic wounds, and inflammatory skin conditions was conducted. Interleukin-17 family signaling is reviewed in the context of tissue repair, and preclinical and clinical studies examining its role in the skin and other organ systems are critically reviewed. The published work supports a pathologic role for interleukin-17 family members in chronic wounds, though this needs to be more conclusively proven. Clinical studies using monoclonal interleukin-17 antibodies to improve healing of chronic skin wounds have not yet been performed, and only a few studies have examined interleukin-17 family expression in chronic skin wounds. Furthermore, different interleukin-17 family members could be playing selective roles in the repair process. These studies suggest a therapeutic role for targeting interleukin-17A to promote wound healing; therefore, interleukin-17A may be a target worthy of pursuing in the near future.
Highlights
More than 9 million people in the United States are diagnosed with chronic wounds, and the incidence rate is expected to grow rapidly with the aging and increasingly diabetic and obese population [1]
All five IL17 receptors share a fibronectin type III (FnIII) extracellular domain and, contrary to other cytokine receptors but similar to toll-like receptors, a cytoplasmic SEF-IL-17R domain [43]. Upon binding to their receptors, IL-17A, IL-17C, and IL-17F induce a conformational change in their receptors that allows heterodimeric complex formation between the specific receptor subunits and subsequently activates Act1, which is an adaptor protein that initiates the mitogen-activated protein kinase (MAPK) and nuclear factor-kB (NF-κB) signaling cascades (Figure 1) [43,44,45,46,47,48,49]
The role of the IL-17 family members in cutaneous disease indicated its potential involvement in the pathogenesis of chronic wounds
Summary
More than 9 million people in the United States are diagnosed with chronic wounds, and the incidence rate is expected to grow rapidly with the aging and increasingly diabetic and obese population [1]. Members of the IL-17 family that are recognized as critical cytokines altering skin function in psoriasis and psoriatic arthritis are IL-17A, IL-17C, and IL17F. These cytokines act on keratinocytes to induce the expression of several chemokines leading to the recruitment and accumulation of neutrophils, T cells, and dendritic cells, Mediators of Inflammation. Lesional skin from antitumor necrosis factor- (TNF-) treated HS patients revealed a reduction in the frequency of TH17 cells and normalization of the TH17 to regulatory T cell ratio [17] This clustering of TH1/TH17associated cytokines around the lesional inflammation has been demonstrated in other studies on HS [18]. The role of the IL-17 family in chronic cutaneous wounds has not been fully determined; the cumulative preclinical and clinical studies in other organ systems suggest that further investigation is warranted to determine its potential as a therapeutic target for chronic wound patients
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