Impact of novel, non-classical type I interferon in HS pathophysiology

PROJECT SUMMARY Hidradenitis Suppurativa (HS) is a chronic, debilitating inflammatory skin disease that affects the pilosebaceous units in skin folds in 1-4% of the population. It often leads to disfiguring and permanent scarring. Histologically, lesions exhibit epidermal hyperplasia, hair follicle abnormalities, and inflammation. HS skin lesions exhibit a diverse immune cell infiltrate and complex cytokine profile, which evolves with disease severity. Current FDA-approved therapies targeting TNF and IL-17A are effective in only 30-40% of patients, leaving many patients without an effective approved therapeutic option. Recently, JAK inhibitors (JAKi) have been successful in clinical trials, but these drugs carry a black box warning, with increased risks of developing serious infections and cardiovascular events. RNA-seq studies demonstrate enhanced action of JAK/STAT- mediated type I interferons (T1-IFNs) in HS lesions. However, the induction, signaling mechanisms, and functional effects of the HS T1-IFN response are unexplored. Our preliminary data reveal for the first time that a single, non-classical T1-IFN subtype, IFN, is selectively induced in HS skin lesions. While signaling by different T1-IFN subtypes is often viewed as redundant, T1-IFN signaling is remarkably plastic, leading to distinct, context-dependent functional effects, like the effects mediated by multiple EGFR ligands on epithelial cells. IFN expression was first identified in other epithelial tissues including the female reproductive tract, nasopharyngeal, lung, and intestinal tissues, but not yet described in skin under any condition. In this proposal, we will identify the unique mechanisms of IFN induction, signaling, and function in HS pathophysiology, which can inform novel therapeutics that better target HS pathophysiology and reduce adverse events (e.g. infection). Specifically, in Specific Aim 1 we will investigate how IFN, versus other T1-IFNs such as IFNs/, is preferentially produced and signals in HS. In Specific Aim 2 we will investigate how IFN can uniquely produce functional effects in keratinocytes and fibroblasts that are critical to HS pathophysiology. Successful completion of this project will elucidate the mechanisms by which a non-classical T1-IFN contributes to the pathogenic cycle of inflammation and tissue disruption in HS. This new knowledge is critical to our overall understanding of HS pathophysiology. The study of non-classical IFNs, like IFN, propels innovative research into understanding the complexities of the T1-IFN response, which has previously focused on IFNs, IFN, and more recently IFN. Considering individual T1-IFNs as distinct and plastic signaling molecules will significantly advance our understanding of their subtype specific skin functions and how IFN uniquely influences HS pathophysiology. This will lay the foundation for potential selective therapeutic interventions. Future therapeutic approaches will result from our efforts to discover new HS pathomechanisms in support of NIAMS goals to improve the treatment for this debilitating disease.