K17 hi Hair Follicle Cells Orchestrate Psoriatic Inflammation Through S100A1-Dependent Signaling
Xin Tang, Pei Qiao, Wanting Liu, Yang Yang, Yunfeng Gu, Xiaojuan Mao, Huiyi Quan, Yixin Luo, Ke Xue, Yanyang Guo, Johann E Gudjonsson, Zhiguo Li, Gang Wang, Shuai ShaoAbstract
Background
Psoriasis is a chronic inflammatory skin disease with frequent and refractory scalp involvement, but the mechanisms underlying regional susceptibility remain unclear.
Objectives
To define the role of hair follicle cell (HFC) subsets in psoriatic inflammation and uncover their pathogenic mechanisms.
Methods
We integrated bulk, single-cell and spatial transcriptomic data from healthy and psoriatic human skin across multiple anatomical sites. HFC subsets and regulatory programmes were profiled through single-cell analyses, and key molecular interactions and functional effects were validated by computational modeling, in vitro assays, and in vivo mouse models.
Results
Five HFC subsets were identified, including K15hi hair follicle stem cells, K17hi, SPINK5hi, K23hi, and MT2Ahi HFCs. Among them, K17hi HFCs were markedly expanded in perilesional and lesional psoriatic skin and were preferentially distributed along a psoriasis-associated pseudotime trajectory enriched for pro-inflammatory programmes. Healthy scalp skin showed increased HFC abundance and preferential enrichment of K17hi HFCs compared with other anatomical sites, which was further enhanced in scalp psoriasis. S100A1, the top differentially expressed gene in K17hi HFCs, was regulated by TCF12 and mediated annexin A2 (ANXA2)-dependent CD4+ T cell activation and tissue-resident memory features. K17 perturbation further supported the upstream regulation of the TCF12-S100A1 axis, whereas ANXA2 blockade attenuated S100A1-induced T-cell responses. Topical S100a1 knockdown alleviated imiquimod (IMQ)-induced psoriasiform inflammation in vivo.
Conclusion
K17 hi HFCs form a region-enriched pro-inflammatory niche that contributes to psoriasis through the TCF12-S100A1-ANXA2 follicular-immune axis. Targeting this axis may provide a potential therapeutic strategy for difficult-to-treat psoriasis.