Targeting CXCR6 suppresses granuloma formation and pulmonary fibrosis through inhibiting Th17 responses in sarcoidosis

Sarcoidosis is a systemic granulomatous disease that often affects the Lungs, Lymph Nodes, and skin. The pathological hallmark of sarcoidosis is the formation of epithelioid, non-necrotizing granulomas, with CD4⁺ T-helper (Th) type 1 (Th1), Th17, and Th17.1 cells scattering throughout the granuloma. The CXCL16-CXCR6 axis plays a crucial role in the development of inflammatory diseases. However, the precise role of CXCR6⁺ CD4⁺ T cells in sarcoidosis pathogenesis and their therapeutic potential remain unclear. In this study, we confirmed the enrichment of CXCR6⁺ CD4⁺ T cells in the lesional tissue of sarcoidosis patients and Propionibacterium acnes-induced sarcoidosis-like model mice. Flow cytometric analysis and single-cell RNA Sequencing revealed that CXCR6⁺ CD4⁺ T cells exhibited a Th17/Th17.1 phenotype and displayed pro-inflammatory characteristics. By performing cell-cell communication analysis and validating the findings with flow cytometry and CXCL16-blockade experiments, we demonstrated an active crosstalk between CXCR6⁺ CD4⁺ T cells and CXCL16⁺ Macrophages in mice. Furthermore, treating mice with an anti-CXCR6 monoclonal antibody effectively reduced the mRNA levels of pro-inflammatory genes, including Nos2, CXCL9, Cxcl10, Il17a, Tnf, and Ifng. In addition, anti-CXCR6 treatment reduced the abundance of Th17 and Th17.1 cells, which was associated with inhibition of downstream mTORC1 signaling. Finally, anti-CXCR6 treatment suppressed granuloma formation and attenuated Collagen deposition in the Lungs. Taken together, our findings highlight CXCR6 as a promising therapeutic target for inhibiting granuloma formation and pulmonary fibrosis in sarcoidosis.