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 CO + 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-gamma, 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-gamma to stimulate human salivary gland epithelial cells (HSGECs) co-cultured with Jurkat cells, and the results showed that CXCL9, 10, 11 was increased by IFN-gamma activating JAK2/STAT1 signal pathway and Jurkat cell 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-gamma stimulating HSGECs, and the CXCL9, 10, 11/CXCR3 axis contributes to the progress of pSS by activating GRK2 to promote T lymphocyte migration.

Automated summary

Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease characterized by dysfunction of secretory glands. This study investigated the role of the CXCL9, 10, 11/CXCR3 axis and GRK2 in promoting T lymphocyte migration in pSS using a mouse model. The results showed increased levels of CO + GRK2 and Th17 + CXCR3, and decreased levels of Treg + CXCR3 in the spleen of NOD mice. In the submandibular gland tissue, there was an increase in IFN-gamma, CXCL9, 10, 11, and infiltration of Th17 cells. In vitro experiments demonstrated that IFN-gamma stimulated HSGECs to increase CXCL9, 10, 11 expression and enhance Jurkat cell migration via GRK2 activation. The findings suggest that the CXCL9, 10, 11/CXCR3 axis contributes to T lymphocyte migration in pSS through GRK2 activation.