CXCL9, 10, 11/CXCR3 axis contributes to the progress of primary Sjogren's syndrome by activating GRK2 to promote T lymphocyte migration

Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that causes dysfunction of secretory glands and the specific pathogenesis is still unknown. The CXCL9, 10, 11/CXCR3 axis and G protein-coupled receptor kinase 2 (GRK2) involved in many inflammation and immunity processes. We used NOD/Ltj mice, a spontaneous SS animal model, to elucidate the pathological mechanism of CXCL9, 10, 11/CXCR3 axis promoting T lymphocyte migration by activating GRK2 in pSS. We found that CD4+GRK2, Th17+CXCR3 was apparently increased and Treg+CXCR3 was significantly decreased in the spleen of 4W NOD mice without sicca symptom compared to ICR mice (control group). The protein levels of IFN-γ, CXCL9, 10, 11 increased in submandibular gland (SG) tissue accompanied by obvious lymphocytic infiltration and Th17 cells overwhelmingly infiltrated relative to Treg cells at the sicca symptom occurs, and we found that the proportion of Th17 cells was increased, whereas that of Treg cells was decreased in spleen. In vitro, we used IFN-γ to stimulate human salivary gland epithelial cells (HSGECs) co-culture with Jurkat cells, and the results showed that CXCL9, 10, 11 was increased by IFN-γ activates JAK2/STAT1 signal pathway and Jurkat cells migration increased with the raised of cell membrane GRK2 expression. HSGECs with tofacitinib or Jurkat cells with GRK2 siRNA can reduce the migration of Jurkat cells. The results indicate that CXCL9, 10, 11 significantly increased in SG tissue through IFN-γ stimulating HSGECs, and the CXCL9, 10, 11/CXCR3 axis contributes to the progress of pSS by activating GRK2 to promote T lymphocyte migration.