CXCR3 blockade impedes the development of Sjögren’s syndrome-like xerostomia in non-obese diabetic mice

Abstract

Abstract The chemokine receptor CXCR3 plays an important role in T cell recruitment in various immune responses and autoimmune diseases. Expression of CXCR3 ligands, including CXCL9, CXCL10 and CXCL11, is elevated in the salivary glands of patients with Sjögren’s syndrome (SS). To elucidate whether interaction between CXCR3 and its ligands is required for the development of SS, we administrated an anti-CXCR3 blocking antibody to non-obese diabetic (NOD) mice, a well-defined model of SS, during the stage prior to disease onset. CXCR3 blockade significantly improved salivary secretion, indicating a remission of SS clinical manifestation. CXCR3 blockade did not affect the gross leukocyte infiltration of the submandibular glands (SMG) as assessed by H&E staining. However, flow cytometric analysis showed that anti-CXCR3 treatment markedly reduced the percentage of CXCR3+CD8 T cells and CD44+CD8 T cells, without affecting that of CXCR3+CD4 T cells and CD44+CD4 T cells in the SMG and submandibular lymph nodes, suggesting a selective effect of CXCR3 blockade on effector T cytotoxic 1 cells. Meanwhile, SMG expression of inflammatory factor TNF-α was markedly diminished by anti-CXCR3 treatment. Consistent with this, CXCR3 blockade significantly enhanced SMG expression of tight junction protein claudin-1 and water channel protein aquaporin-5, two factors that are crucially required for normal salivary secretion and can be down-regulated by TNF-α. Taken together, our findings demonstrated that the interaction between endogenous CXCR3 and its ligands plays a proinflammatory and pathogenic role in the development of SS-like xerostomia in NOD mouse model.