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CXCL9, 10, 11/CXCR3 Axis Contributes to the Progress of Primary Sjogren’s Syndrome by Activating GRK2 to Promote T Lymphocyte Migration

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Abstract

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-cultured with Jurkat cells, and the results showed that CXCL9, 10, 11 was increased by IFN-γ 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-γ stimulating HSGECs, and the CXCL9, 10, 11/CXCR3 axis contributes to the progress of pSS by activating GRK2 to promote T lymphocyte migration.

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Funding

This study was supported by the National Nature Science Foundation of China (Nos. 81973332 and 81302784), Research Fund of Anhui Institute of translational medicine (2021zhyx-C24), Doctoral Research Grant Fund of Anhui Medical University (XJ201938), 2021 Anhui Medical University Discipline Construction Project (Surgery and Pharmacology Co-construction Project), and 2022 Anhui Provincial Natural Science Foundation (2208085MH283).

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Authors and Affiliations

  1. Institute of Clinical PharmacologyKey Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune MedicineShushan District, Anhui Medical University, 81# Meishan Road, 230032Anhui Province, Hefei City, China

    Jing Zhang, Xiao Zhang, Yuqi Liu, Danqian Cheng, Qianwen Tian, Wei Wei & Huaxun Wu

  2. Department of Neurosurgery, The Affiliated Chuzhou Hospital of Anhui Medical University, The First People’s Hospital of Chuzhou, 12 Zhongyou Road, Chuzhou, 239001, China

    Xingjie Shi & Ning Lin

  3. Anhui Provincial Institute of Translation Medicine, Hefei, 230032, China

    Huaxun Wu

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  1. Jing Zhang
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Contributions

JZ, XZ, XJS, YQL, QWT, and DQC conducted the study and analyzed the data, JZ, NL, and HXW provided expertise for design of the study and drafted the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

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Correspondence to Ning Lin, Wei Wei or Huaxun Wu.

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Zhang, J., Zhang, X., Shi, X. et al. CXCL9, 10, 11/CXCR3 Axis Contributes to the Progress of Primary Sjogren’s Syndrome by Activating GRK2 to Promote T Lymphocyte Migration. Inflammation 46, 1047–1060 (2023). https://doi.org/10.1007/s10753-023-01791-9

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