High IL-17E and Low IL-17C Dermal Expression Identifies a Fibrosis-Specific Motif Common to Morphea and Systemic Sclerosis

Abstract

BackgroundHigh interleukin (IL)-17A levels are characteristically found in the skin of systemic sclerosis (SSc) individuals. Our aim was to investigate whether the dermal expression of IL-17A and related IL-17 family members (i.e. IL-17C, IL-17E and IL-17F) could distinguish fibrotic from healthy skin and could show similarities in SSc and morphea, two disorders with presumed distinct pathogenesis, but characterized by skin fibrosis.MethodsBiopsies were obtained from the involved skin of 14 SSc, 5 morphea and 8 healthy donors (HD) undergoing plastic surgery. Immunohistochemistry/immunofluorescence techniques were coupled to a semi-automated imaging quantification approach to determine the presence of the IL-17 family members in the skin. The in vitro effects induced by the IL-17 family members on fibroblasts from normal and SSc individuals were assessed by ELISA and RIA.ResultsPositive cells for each of the IL-17 isoforms investigated were present in the dermis of all the individuals tested, though with variable frequencies. SSc individuals had increased frequency of IL-17A+ (p = 0.0237) and decreased frequency of IL-17F+ (p = 0.0127) and IL-17C+ cells (p = 0.0008) when compared to HD. Similarly, morphea individuals had less frequent IL-17C+ cells (p = 0.0186) in their skin but showed similar number of IL-17A+ and IL-17F+ cells when compared to HD. Finally, IL-17E+ cells were more numerous in morphea (p = 0.0109) and tended to be more frequent in SSc than in HD. Fibroblast production of IL-6, MMP-1 and MCP-1 was enhanced in a dose-dependent manner in the presence of IL-17E and IL-17F, but not in the presence of IL-17C. None of the cytokine tested had significant effect on type I collagen production. Of interest, in SSc the frequency of both IL-17A and IL-17F positive cells increased with disease duration.ConclusionsThe frequency of IL-17A and IL-17F distinguish SSc to morphea individuals while dermal expression of IL-17C (low) and IL-17E (high) identifies a fibrosis-specific motif. The specific IL-17C/IL-17E cytokine combination may thus play a role in the development of fibrosis.

Keratinocyte-Derived IL-17E Contributes to Inflammation in Psoriasis

“…IL-17E-transgenic mice, in addition to other features, exhibit increased neutrophil counts (Pan et al, 2001), and IL-17E favors the production of TNF-α and innate immune cellrecruiting chemokines, such as IL-8 and MCP-1 in several cell types (Lee et al, 2004;Letuve et al, 2006;Lonati et al, 2014;Wong et al, 2005). The positive correlation we observed in psoriatic skin between the number of IL-17E+ cells and the number of neutrophils further strengthens the relevance of these biological functions.…”

“…A C C E P T E D ACCEPTED MANUSCRIPT 11 2013) and to favor the production of TNF-α and other pro-inflammatory chemokines by fibroblasts (Lee et al, 2004;Letuve et al, 2006;Lonati et al, 2014). In addition, we report here that macrophages are target of IL-17E in the skin, and macrophages were shown to play a key role in the pathogenesis of psoriasiform skin inflammation in mouse models (Clark and Kupper, 2006) The efficient up take of IL-17E by macrophages in psoriatic skin may represent a physiological attempt to clear IL-17E from the extracellular environment, as observed for other cytokines (Lindemann et al, 2008).…”

The role of the acquired immune response in systemic sclerosis

“…Others have found that IL-17A failed to increase type I and type III procollagen mRNA expressions in fibroblasts from healthy controls and SSc patients [56]. Our own findings support the contention that IL-17A does not favor type I collagen production by healthy and SSc fibroblasts but rather limits the transdifferentiation of fibroblasts into pro-fibrotic myofibroblasts, simultaneously favoring the production of IL-8, IL-6, MCP-1, and MMP-1 [15, 63,108]. Thus, the bulk of evidence in humans, as opposed to rodents, indicates that IL-17 and in particular IL-17A simultaneously exert anti-fibrotic and pro-inflammatory activities, which net result may be that of containing rather than enhancing extracellular matrix (ECM) deposition (Fig.…”

“…While the frequency of Th17 lymphocytes is low in the peripheral blood of healthy individuals (~1 %), this subset undergoes recruitment and expansion in sites of active inflammation and tissue damage [4]. Increased levels of IL-17 and Th17 cells have been found in the peripheral blood as well as within target tissues (i.e., the skin) of SSc patients particularly during early phases and in association with ILD [27, 62,63,73,86,89,106,108,120]. In addition, cytokines crucial for Th17 T cell priming and expansion such as IL-6 and IL-23 have been reported enriched in SSc subjects, and a polymorphism of the IL-23 receptor gene (IL23R) has shown association with diffuse SSc and antitopoisomerase 1 positivity [1, 41, 50].…”

“…In addition to IL-17A, other members of the IL-17 family have been documented in SSc, including IL-17F, IL-17C, and IL-17E (also known as IL-25). High IL-17E and low IL-17C dermal expression characterizes SSc as well as morphea when compared to healthy skin, thus suggesting that this expression pattern may be functionally linked to skin fibrosis [63]. However, since IL-17C does not directly act on fibroblasts and IL-17E enhances fibroblast inflammatory responses rather than collagen deposition, it could be possible that their effects are mediated by third party cells, including keratinocytes and macrophages.…”