Neutralization of IL-17C Reduces Skin Inflammation in Mouse Models of Psoriasis and Atopic Dermatitis

Abstract

IL-17C is a functionally distinct member of the IL-17 family that was believed to play a role in the pathogenesis of psoriasis. Here we confirmed that IL-17C is involved in psoriasis and explored potential roles for IL-17C in atopic dermatitis (AD). An anti-IL-17C antibody, MOR106, was generated that potently and selectively binds to human and mouse IL-17C, thereby inhibiting the binding of IL-17C to its IL-17RE receptor. The antibody inhibited cutaneous inflammation in an IL-23-induced psoriatic-like skin inflammation model. In lesional skin of patients with AD, IL-17C expression levels were increased and localized to keratinocytes and infiltrating immune cells. To determine the contribution of IL-17C to AD pathogenesis, MOR106 was tested in two distinct in vivo models. In the calcipotriol-induced AD model, ear skin inflammation, TSLP, and IL-33 protein production in ears was suppressed by MOR106. Consistently, in the flaky tail strain mouse model, spontaneous development of AD-like skin inflammation was reduced by MOR106. Moreover, serum IgE levels, number of mast cells in skin and T helper type 2-related cytokines IL-4 and CCL17 in serum were all reduced. Overall, our results indicate that IL-17C is a central mediator of skin inflammation beyond psoriasis and is relevant in particular in AD.

IL‐17C amplifies epithelial inflammation in human psoriasis and atopic eczema

“…Of note, IL‐17C induced chemokines of Th1 (CXCL10), Th2 (CCL5) and Th17 immunity (CXCL8), thus pointing out that IL‐17C is not exclusively related to one specific type of T cell‐mediated inflammation. Recently it was shown that depletion of IL‐17C signalling decreases inflammation in murine models of ISD . Based on the mechanistic data obtained in our cell culture experiments, we could prove the pivotal role of IL‐17C for immune cell recruitment in these murine models as we demonstrate that blockade of IL‐17C resulted in significantly reduced T cell, neutrophil and eosinophil numbers.…”

“…MOR106 is a novel, fully‐human anti‐IL‐17C IgG1 antibody, which selectively inhibits the binding of IL‐17C to the IL‐17RA/IL‐17RE receptor heterodimer in humans and mice. Recently, it was shown that MOR106 attenuates skin inflammation in murine models of AE and psoriasis in terms of epidermal thickness and cytokine expression in the skin . However, it remained elusive how IL‐17C depletion affects immune cell composition in these models.…”

“…IL‐17C is required for sufficient control of intestinal infections, but dispensable for the control of candida infections . Neutralization of IL‐17C reduces ear thickness and expression of inflammatory genes in mouse models of psoriasis and atopic eczema (AE) . The role of IL‐17C in human ISD and the way how IL‐17C influences skin inflammation, however, are still elusive.…”

“…7 Neutralization of IL-17C reduces ear thickness and expression of inflammatory genes in mouse models of psoriasis and atopic eczema (AE). 8 The role of IL-17C in human ISD and the way how IL-17C influences skin inflammation, however, are still elusive.…”

Chitinase 3‐like 1 drives allergic skin inflammation via Th2 immunity and M2 macrophage activation

“…It is characterized by complex interactions between environmental and genetic factors, including a skin barrier defect, Th2 inflammation with elevated serum IgE and eosinophilia . Classically, AD is associated with the Th1/ Th2 immune response; however, there is growing evidence that Th17 and Th22 inflammatory responses are also involved . One of the most well‐known risk factors for AD is a mutation of filaggrin (Flg) gene which is important for skin barrier .…”