CXCR6 sustains TRM-driven psoriasis relapse by CXCL16 chemotaxis and curcumol targeting

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease characterized by a high relapse rate, primarily driven by tissue-resident memory T cells (TRM). OBJECTIVES: This study aims to elucidate that the CXCR6/CXCL16 axis is a key regulator of TRM persistence and psoriasis relapse, and demonstrates that curcumol can mitigate psoriasis relapse via this axis and TRM modulation. METHODS: By integrating single-cell RNA sequencing, spatial transcriptomics, and a CXCR6-knockout mouse model, we analyzed the characteristics of TRM cell subsets and the functional role of CXCR6 in psoriatic lesions. Using imiquimod-induced mouse models of psoriasis onset and relapse, we evaluated the impact of CXCR6 knockdown on TRM cell retention and inflammatory responses. Through in vitro cell experiments, immunofluorescence, and flow cytometry, we validated the inhibitory effect of curcumol on the CXCL16-CXCR6 axis and its role in suppressing TRM cell differentiation. Clinical sample analysis further confirmed the expression pattern of CXCR6 in recurrent psoriatic lesions. RESULTS: TRM cells, particularly the Tc17 subset, exhibit elevated CXCR6 expression in recurrent psoriatic lesions and drive inflammation via the TNF/CCL signaling network. CXCR6 knockout significantly ameliorates the psoriatic immune microenvironment by reducing TRM retention and disease relapse. Experimental studies on curcumol demonstrate that it inhibits CXCL16-CXCR6 interaction, downregulates pro-inflammatory cytokines, and diminishes TRM persistence, while maintaining anti-relapse efficacy even after treatment cessation. CONCLUSION: These research findings further validate the critical role of TRM cells in the relapse of psoriasis and suggest the potential value of curcumol as a CXCR6-targeted therapeutic agent in preventing the relapse of psoriasis. This study integrates mechanistic exploration with translational innovation, providing a new therapeutic strategy to address the clinical challenge of psoriasis relapse.