IL-17 in inflammatory skin diseases psoriasis and hidradenitis suppurativa

Abstract

The skin is one of the most important organs in the body, providing integrity and acting as a barrier to exclude microbes, allergens and chemicals. However, chronic skin inflammation can result when barrier function is defective and immune responses are dysregulated or misdirected against harmless or self-antigens. During the last 15 years interleukin (IL)-17 cytokines have emerged as key players in multiple inflammatory disorders, and they appear to be especially prominent in skin inflammation. IL-17 cytokines produced by T cells and other cell types potently activate keratinocytes to promote inflammation in a feed-forward loop. Given this key pathogenic role of the IL-17 pathway in autoimmune and inflammatory disease, it has been the focus of intense efforts to target therapeutically. The inflammatory effects of IL-17 can be targeted directly by blocking the cytokine or its receptor, or indirectly by blocking cytokines upstream of IL-17-producing cells. Psoriasis has been the major success story for anti-IL-17 drugs, where they have proven more effective than in other indications. Hidradenitis suppurativa (HS) is another inflammatory skin disease which, despite carrying a higher burden than psoriasis, is poorly recognized and under-diagnosed, and current treatment options are inadequate. Recently, a key role for the IL-17 pathway in the pathogenesis of HS has emerged, prompting clinical trials with a variety of IL-17 inhibitors. In this review, we discuss the roles of IL-17A, IL-17F and IL-17C in psoriasis and HS and the strategies taken to target the IL-17 pathway therapeutically.

Keywords: IL-17; hidradenitis suppurativa; psoriasis.

Fig. 1

Cellular sources and targeting of interleukin (IL)‐17. IL‐17A and IL‐17F are the signature cytokines of the T helper type 17 (Th17) cell subset. They may also be produced by CD8 T cells and innate‐like lymphoid cells, including innate lymphoid cells (ILC), invariant natural killer T (iNKT) cells and γδ T cells. IL‐17 expression by myeloid cells including neutrophils and mast cells is suggested but not universally accepted. Dimers of IL‐17A, IL‐17F or IL‐17A/F bind to their IL‐17 receptor (IL‐17RA/RC), which is expressed on epithelial cells. IL‐17C is produced by epithelial cells and binds to IL‐17RA/RE. IL‐17R signalling results in the expression of anti‐microbial peptides, inflammatory cytokines and chemokines that promote inflammation via the recruitment of neutrophils and other immune cells. The inflammatory effects of IL‐17 signalling have been targeted directly via monoclonal antibody blockade of IL‐17A (secukinumab, ixekizumab), IL‐17A/F (bimekizumab) or the IL‐17 receptor IL‐17RA (brodalumab). Alternatively, the pathway can be targeted upstream of Th17 cells by blocking IL‐23 alone via its specific p19 subunit (guselkumab, tildrakizumab, risankizumab), or both IL‐23 and IL‐12 via the common p40 subunit (ustekinumab).

Fig. 2

Schematic representation of psoriasis pathogenesis. Psoriasis is triggered in genetically susceptible individuals by environmental factors and/or breakdown of tolerance to self‐antigens. For example, release of self‐DNA molecules together with the anti‐microbial peptide LL‐37 activates plasmacytoid dendritic cells (pDC) to produce interferon (IFN)‐α. IFN‐α, together with tumour necrosis factor (TNF) activates myeloid DC which present self‐antigens to T cells, which then differentiate into T helper type 1 (Th1) and Th17 cells via IL‐12/IFN‐γ and IL‐23/IL‐1β/IL‐6, respectively. Th17 cells migrate to the dermis via the keratinocyte‐derived chemokines chemokine (C‐C motif) ligand 20 (CCL20) and chemokine (C‐X‐C motif) ligand (CXCL) 9/10/11, where they secrete homodimers or heterodimers of IL‐17A and IL‐17F and IL‐22. IL‐17A/F and IL‐22 bind to their receptors on both keratinocytes and fibroblasts and synergize with TNF to induce proliferation and expression of anti‐microbial peptides, such as β‐defensins and S100A7‐9, and a range of cytokines and chemokines. Chemokines such as IL‐8 and CXCL1/3/5/8 recruit neutrophils, whilst cytokines IL‐17C and IL‐36 induce further activation and proliferation of keratinocytes in an inflammatory loop. IL‐1β and TNF production by keratinocytes induces fibroblasts to release keratinocyte growth factor (KGF) and epidermal growth factor (EGF) which act back on keratinocytes, further contributing to their activation and proliferation. Meanwhile, keratinocyte‐derived IL‐1β, IL‐6 and IL‐17C feedback to further activate DC and Th17 cells.

Fig. 3

Schematic representation of hidradenitis suppurativa (HS) pathogenesis. Follicular obstruction is an essential event for the development of HS, followed by cyst formation which may rupture and trigger a potent immune response and ongoing inflammation. Genetic aberrations and/or dysfunctional keratinocyte stem cells, dysregulated microbiome, smoking, obesity and mechanical stress are thought to promote follicular occlusion and inflammation. Nucleotide‐binding domain‐like receptor protein 3 (NLRP3) activation and interleukin (IL)‐1β production are key features and may be driven by smoking, a dysregulated microbiome or damage‐associated molecular patterns (DAMP) released upon cyst rupture. Activated dendritic cells (DC) drive the differentiation of CD4 T cells into T helper type 1 (Th1) and Th17 subsets. Th1 cells can activate neutrophils to undergo NETosis, releasing proinflammatory cytokines and activating the NLRP3 inflammasome. Th17 cells, driven by IL‐1β and IL‐23, produce IL‐17A and IL‐17F, which potently activate keratinocytes. Activated keratinocytes release anti‐microbial peptides and chemokines such as IL‐8, which recruit neutrophils. In addition, cytokines, including IL‐17C and IL‐36 secreted by the keraitnocytes act in an autocrine manner to further potentiate their activation and proliferation. Smoking and inflammation cause citrullination of proteins which may be the target of a B cell response and production of anti‐citrullinated protein antibodies (ACPA) that contribute to the inflammatory response. In the later stages, keratinocytes tunnel to form sinus tracts which are susceptible to infection and can exacerbate inflammation.