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. Overall design: Single-cell RNA sequencing of isolated CD45? immune cells from both scalp and body lesions of psoriasis (n = 3), and single-cell RNA sequencing of scalp of healthy controls (n = 5).