{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T15:25:09Z","timestamp":1780327509540,"version":"3.54.1"},"posted":{"date-parts":[[2026,3,25]]},"group-title":"Immunology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Therapeutic blockade of IL-17 and TNF can effectively treat inflammatory skin diseases such as 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 is frequently used to model psoriasis. Here, we demonstrate that intradermal injection of recombinant IL-17 and TNF elicits skin inflammation with features of hidradenitis suppurativa, including a gene expression program that is distinct from psoriasis and imiquimod-induced inflammation. Single-cell transcriptomic network analysis identified dermal fibroblasts as the dominant cell communication hub in hidradenitis suppurativa and in mice injected with IL-17 and TNF. In contrast, fibroblasts and keratinocytes both show strong network involvement in psoriasis and in mice challenged with imiquimod. Cell-type-specific deletion of IL-17 receptor A in mice revealed that imiquimod-induced inflammation depends equally on IL-17 signaling in fibroblasts and keratinocytes, whereas inflammation induced by intradermal IL-17 and TNF only requires fibroblasts to recognize IL-17 and is independent of keratinocyte IL-17 sensing. Single-cell transcriptomic analysis of these conditional knockout mice further demonstrated that keratinocytes and fibroblasts activate divergent and disease-dependent transcriptional programs following activation by IL-17. Together, these findings introduce a new 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.<\/jats:p>","DOI":"10.64898\/2026.03.23.713409","type":"posted-content","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T04:26:10Z","timestamp":1774499170000},"source":"Crossref","is-referenced-by-count":1,"title":["Disease context dictates the cellular targets of IL-17 in inflammatory skin disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4160-6394","authenticated-orcid":false,"given":"Kellen J.","family":"Cavagnero","sequence":"first","affiliation":[{"name":"Department of Dermatology, UC San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengwu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology, UC San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Dermatology, UC San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Aguilera","sequence":"additional","affiliation":[{"name":"Department of Dermatology, UC San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Kirma","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Bogel","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Michelle","family":"Kahlenberg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lam C.","family":"Tsoi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann E.","family":"Gudjonsson","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan"},{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Gallo","sequence":"additional","affiliation":[{"name":"Department of Dermatology, UC San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032712453569000_2026.03.23.713409v1.1","doi-asserted-by":"publisher","DOI":"10.2147\/CCID.S420850"},{"key":"2026032712453569000_2026.03.23.713409v1.2","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1016\/j.jid.2025.04.009","article-title":"Differentiating the Role of Inflammation in Hidradenitis Suppurativa from that in other Inflammatory Skin Diseases","volume":"145","year":"2025","journal-title":"J Invest Dermatol"},{"key":"2026032712453569000_2026.03.23.713409v1.3","first-page":"1110","article-title":"Imiquimod-Induced Psoriasis in Mice Depends on the IL-17 Signaling of Keratinocytes","volume":"13","year":"2019","journal-title":"J Invest Dermatol"},{"key":"2026032712453569000_2026.03.23.713409v1.4","doi-asserted-by":"crossref","unstructured":"Liu, T. et al. 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