Targeting fibroblast TNF receptor 1 attenuates type 17 skin inflammation

Inflammation at epithelial barriers involves a complex cell communication network, with subsets of fibroblasts increasingly recognized as active players in immune cell recruitment. To investigate the role of fibroblasts in interleukin (IL)-17-mediated skin diseases, we analyzed single-cell transcriptomic data from human psoriatic skin and identified tumor necrosis factor (TNF) recognition by TNF receptor 1 (TNFR1) as the most upregulated pathway in immune-acting fibroblasts. Functionally, TNF induced TNFR1-dependent neutrophil chemokine expression in cultured fibroblasts. Transcriptomics of skin from patients treated with TNF inhibitors revealed that expression of fibroblast-derived neutrophil chemokines depends on TNF. To test the significance of TNF recognition by fibroblasts, we developed mice lacking TNFR1 specifically in fibroblasts that showed impaired neutrophil recruitment to the skin after intradermal IL-17A and TNF injection and topical imiquimod treatment. This study establishes TNF signaling in immune-acting fibroblasts as a key driver of type 17 skin inflammation, challenging the prevailing view that TNF acts predominantly through keratinocytes.