IL-17 elicits skin inflammation by acting on different cell types depending on disease context

Summary: Abstract Body: Therapeutic blockade of IL-17 is highly effective in treating inflammatory skin conditions, but the mechanisms responsible for efficacy are incompletely understood. IL-17 synergizes with PAMPs, DAMPs, and cytokines—especially TNFα—to induce neutrophil chemokine expression and drive tissue inflammation. While keratinocytes have been considered the primary targets of IL-17, we recently showed that subsets of immune-acting fibroblasts in the dermis are also key targets. Here, we evaluated the relative importance of fibroblasts versus keratinocytes in driving type 17 inflammation in skin. Single-cell transcriptomics of healthy human and mouse skin show that keratinocytes and fibroblasts express similarly high levels of IL-17 and TNFα receptors. Functional experiments with primary cultured cells demonstrate that both cell types recognize IL-17 and TNFα but that fibroblasts are induced to express 5-fold more neutrophil chemokine Cxcl1 than keratinocytes (P<0.0001). To evaluate the relative role of each cell type, we developed conditional knockout mice lacking the IL-17 receptor specifically in fibroblasts (Pdgfra△Il17ra) or keratinocytes (Krt14△Il17ra) and exposed these mice to topical or intradermal stimuli. Skin neutrophilia induced by intradermal injection of IL-17 and TNFα was reduced by 80% in Pdgfra△Il17ra mice (P<0.01) but was unchanged in Krt14△Il17ra mice. Conversely, skin neutrophilia after topical imiquimod was reduced by 50% in Pdgfra△Il17ra mice (P<0.01) and by 50% in Krt14△Il17ra mice (P=0.06). Immunostaining showed CXCL1 protein expression by keratinocytes was more abundant in response to topical stimuli (imiquimod, C. albicans) compared to intradermal ones (IL-17/TNFα, S. aureus, C. acnes). Additionally, neutrophil migration to the epidermis was more pronounced with topical stimuli than intradermal ones. Collectively, these findings demonstrate that IL-17 drives skin inflammation through context-dependent cellular targets, with fibroblasts and keratinocytes playing distinct roles based on the depth of inflammatory stimulus. Kellen Cavagnero¹, Fengwu Li¹, Carlos Aguilera¹, Brittany Crown¹, Richard L. Gallo¹ 1. University of California San Diego, La Jolla, CA, United States. Translational Studies: Preclinical