Disease context dictates the cellular targets of IL-17 in inflammatory skin disease.

IL-17 and TNF blockade effectively treats hidradenitis suppurativa and psoriasis, yet the relative importance of the different cell types that respond to IL-17 and TNF remains unresolved. Keratinocytes are viewed as the dominant effector cells, whereas fibroblasts have recently emerged as important contributors. In mice, topical imiquimod induces IL-17- and TNF-dependent skin inflammation and models psoriasis. Here, we demonstrate that intradermal injection of IL-17 and TNF elicits inflammation with features of hidradenitis suppurativa, including a transcriptional program that is distinct from that in psoriasis and imiquimod-induced inflammation. Single-cell transcriptomic network analysis identified fibroblasts as the dominant communication hub in hidradenitis suppurativa and in IL-17/TNF-injected mice. In contrast, both fibroblasts and keratinocytes showed strong network involvement in psoriasis and imiquimod-treated mice. Cell-type-specific deletion of IL-17RA revealed that imiquimod-induced inflammation depends equally on IL-17 signaling in fibroblasts and keratinocytes, whereas inflammation induced by intradermal IL-17/TNF requires only fibroblasts to recognize IL-17. Single-cell transcriptomic analysis of conditional knockout mice demonstrated that keratinocytes and fibroblasts activate divergent and disease-dependent transcriptional programs downstream of IL-17. These findings introduce a conceptual framework wherein IL-17 signaling is routed through distinct cellular and molecular pathways depending on disease context and establish complementary experimental systems for interrogating type 17 skin inflammation.