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

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: macrophages promote T and B cell migration in vitro. CONCLUSION: T cells and B cells in salivary glands aggravate SS pathogenesis, suggesting CCR1/CCL5 as a novel target to treat SS.