The roles of interleukin (IL)-17A and IL-17F in hidradenitis suppurativa pathogenesis: evidence from human in vitro preclinical experiments and clinical samples

Background Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease associated with significant comorbidities and poor quality of life. Despite uncertainty about pathways driving inflammation in HS lesions, the cytokines interleukin (IL)-17A and IL-17F have been shown to be upregulated in patients with HS. Previous studies have demonstrated that the monoclonal IgG1 antibody bimekizumab selectively inhibits IL-17F in addition to IL-17A.Objectives To further investigate the roles of IL-17A and IL-17F in HS pathogenesis.Methods RNA sequencing (RNAseq) was conducted on skin biopsies taken at baseline and after treatment at week 12 of a phase II proof-of-concept study of bimekizumab in patients with moderate-to-severe HS. Differentially expressed genes were identified between baseline lesional and nonlesional samples and between lesional samples before and after bimekizumab treatment, to describe molecular disease mechanisms and treatment effect. Human hair follicular keratinocytes (HHFK) were cultured and treated with a supernatant of stimulated T helper (Th)17 cells in combination with anti-IL-17A, anti-IL-17F, anti-IL-17A and anti-IL-17F, or IgG control antibodies. Total mRNA was analysed by RNAseq. Cellular supernatants from the stimulated HHFKs were used as a source of Th17-induced chemoattractants in neutrophil chemotaxis assays.Results RNAseq revealed that the most prominently upregulated genes in HS lesions included those associated with neutrophil biology. Bimekizumab treatment resulted in reduced expression of these genes. The extent of reduction in gene expression was dependent on achieving HiSCR50 (>= 50% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining tunnel count). In vitro dual inhibition of IL-17A and IL-17F had greater attenuation of Th17-induced HS-associated genes and neutrophil migration in HHFKs vs. IL-17A or IL-17F inhibition alone. In situ hybridization found that IL-17A- and IL-17F-producing cells in HS lesions can lack the IL-23 receptor and IL-1 beta could induce IL-23-independent IL-17F expression in vitro. Furthermore, mucosal-associated invariant cells in HS tunnels expressed IL-17F and IL-1 receptor type 1. IL-1 beta-, IL-17A- and IL-17F-expressing cells were found to be co-localized in HS lesions.Conclusions These data support the hypothesis that IL-17A and IL-17F play central roles in HS, a neutrophilic dermatosis. The presence of IL-1 beta may partly explain the high expression of IL-17F in lesional HS tissue. We identified a number of differentially expressed genes between lesional and nonlesional skin in patients with moderate-to-severe hidradenitis suppurativa (HS) that could be modulated by the IL-17A and IL-17F inhibitor bimekizumab. IL-17A and IL-17F protein expression were elevated in HS lesional tissue vs. nonlesional skin, and IL-17-expressing IL-23R-negative cells were identified in HS lesions. IL-1 beta may be an important IL-23-independent driver of IL-17A, particularly IL-17F in HS lesions. Together, these data support the hypothesis that IL-17A and IL-17F play a central role in this neutrophilic dermatosis and that the presence of IL-1 beta may partly explain the high expression of IL-17F in lesional HS tissue. Hidradenitis suppurativa (or 'HS' for short) is a long-term skin condition that affects between 4 and 10 in every 1,000 people worldwide. People with HS develop painful lumps and swollen, painful pockets of pus-filled skin. Therefore, some people with HS can experience a poor quality of life. Some options for treatment are available. However, not all people have the same response or results from treatment, so we need to understand more about how HS starts.Interleukins ('IL' for short) are proteins made by cells of the immune system and some other cells. Genes are the instructions to make these proteins. When a certain gene is activated, it makes more of that protein. Other research has shown that two types of interleukins called IL-17A and IL-17F recruit inflammation-causing cells and may be involved in HS.This study was carried out in the UK and looked at the roles of IL-17A and IL-17F in HS. We analysed skin samples from patients with HS. We compared diseased skin samples against healthy areas of skin. In diseased skin, we found that many molecules associated with recruiting inflammation-causing cells, including IL-17A and IL-17F, were more common. In diseased skin, the genes coding for these proteins were upregulated. Bimekizumab is a drug that blocks IL-17F in addition to IL-17A. Treatment with bimekizumab helped lower these genes closer to a normal level.Our results show that IL-17A and IL-17F play an important role in HS and could contribute to developing new and better treatments for people living with the skin condition.