Single-cell RNA Sequencing Reveals Trem2⁺ Macrophages Enriched in the Scalp Induce Tc17 Cell Activation to Promote Psoriatic Inflammation

Background: Scalp psoriasis presents distinct clinical features and treatment resistance compared to lesions on other body sites, yet its immune landscape remains poorly characterized. Methods: We performed single-cell RNA sequencing (scRNA-seq) on CD45⁺ immune cells from scalp and body plaque lesions of psoriasis patients and healthy controls. A total of 41,438 immune cells were analyzed. Downstream analyses included clustering, gene set enrichment, pseudotime trajectory inference, and cell–cell interaction modeling. Multiplex immunofluorescence was used to validate spatial co-localization. Results: Scalp psoriasis lesions exhibited a higher abundance of IL17⁺ CD8⁺ tissue-resident memory T (Tc17) cells, which co-expressed IFNG and lipid transporter FATP2 (SLC27A2). Pseudotime analysis revealed a trajectory from IL7R⁺ Trm cells toward Tc17 cells, especially enriched in the scalp. Trem2⁺ macrophages in scalp lesions showed increased expression of inflammatory mediators and MHC-I molecules. CellChat revealed enhanced MHC-I–mediated interactions between Trem2⁺ macrophages and Tc17 cells in the scalp. These interactions were confirmed by immunofluorescence, demonstrating co-localization of FATP2⁺ Tc17 and Trem2⁺ macrophages around sebaceous units. Conclusions: This study defines a scalp-specific pathogenic axis involving Trem2⁺ macrophages and FATP2⁺ Tc17 cells, potentially explaining the localization and persistence of inflammation in scalp psoriasis. Targeting lipid metabolism or specific cell–cell interactions may provide new therapeutic avenues for treatment-resistant scalp psoriasis.