CCR1hi/CCL5hi macrophage-mediated CCL5hi T cell chemotaxis in salivary gland aggravates Sjögren’s syndrome

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Introduction CCR1 upregulation in macrophages promotes sequential T/B-cell infiltration via CCL5-mediated crosstalk, aggravating salivary gland damage in Sjögren’s syndrome (SS), implicating CCR1/CCL5 as potential therapeutic targets. Objectives To investigate the role of CCR1/CCL5 in salivary gland lymphocytic infiltration and SS progression. Methods Functional enrichment analysis was performed on four bulk RNA-seq datasets to identify common immune pathways, highlighting CCR1 as a key factor. Cytohubba and STRING analyses identified CCL5 as the primary ligand for CCR1 in SS salivary glands. Single-cell RNA sequencing (scRNA-seq) and temporal analyses were performed for the cellular distribution of CCR1 and CCL5, their interactions, and sequential immune cell infiltration, and further validated using multiplex immunofluorescence (mIF) in SS patients and Non Obese Diabetes (NOD) mice salivary glands. The effect of CCR1 inhibition on SS progression was assessed in NOD mice. Results We observed CCR1 overexpressed (CCR1 hi ) macrophages and CCL5 overexpressed (CCL5 hi ) macrophages and T cells in SS salivary glands. Temporal analysis revealed that CCR1 hi /CCL5 hi macrophages first infiltrated and recruited CCL5 hi T cells, followed by B cells in SS salivary glands. Interaction analysis demonstrated strong autocrine signaling in CCR1 hi /CCL5 hi macrophages and significant crosstalk between CCR1 hi /CCL5 hi macrophages, CCL5 hi T cells, and B cells. Functional enrichment indicated that CCR1 hi /CCL5 hi macrophages recruit and activate CCL5 hi T cells via chemokine signaling, and CCL5 hi T cells, in turn, recruit and activate B cells. mIF confirmed these findings in SS patients and NOD mice. CCR1 inhibition in NOD mice alleviated lymphocytic infiltration, glandular destruction, and xerostomia. CCR1 hi /CCL5 hi macrophages promote T and B cell migration in vitro . Conclusion We revealed that CCR1 hi /CCL5 hi macrophages-mediated recruitment and activation of CCL5 hi T cells and B cells in salivary glands aggravate SS pathogenesis, suggesting CCR1/CCL5 as a novel target to treat SS.