Targeting EZH2 prevents the occurrence and mitigates the development of Sjögren's syndrome in mice

Int Immunopharmacol. 2022 Sep;110:109073. doi: 10.1016/j.intimp.2022.109073. Epub 2022 Jul 21.

Abstract

Objective: We analyzed RNA-SEQ data and found that EZH2 gene expression in salivary glands (SGs) of Sjögren's syndrome (SS) patients was up-regulated and correlated with pathological injury. In this study, we sought to determine if inhibiting EZH2 would ameliorate SS-like disease in NOD/Ltj (NOD) mice.

Methods: We analyzed RNA-SEQ data of SGs of patients with SS from data obtained from the GEO database to explore the correlation between EZH2 gene expression and the progression of SS. Inhibition of EZH2 in the NOD mice was achieved by intraperitoneal administration of GSK343 using both a preventative and a therapeutic model. The effects of GSK343 on SGs secretion and pathological damage, as well as the levels and functions of T cells, B cells, Myeloid-derived suppressor cells (MDSCs), and other immune cells were evaluated.

Results: The expression levels of the gene encoding EZH2 in the SGs of SS patients were significantly higher than the non-SS sicca patients, and the expression levels were positively correlated with the severity of the SGs pathological damage. GSK343 treatment significantly increased the salivary flow rate and pathological damage of the SGs in the NOD mice compared to the control mice. In addition, GSK343 significantly inhibited the number and pro-inflammatory-factor secretion of CD4+ and CD8+ T cells and inhibited the increase in the Th1/Th2 cell ratio caused by SS. RNA-SEQ data also showed that EZH2 inhibited several inflammatory pathways during the pathogenesis of SS.

Conclusions: EZH2 expression was up-regulated in the submandibular gland tissue of SS patients.Inhibition of EZH2 alleviated SS-like disease in NOD mice, suggesting that EZH2 might be a potential target for the clinical treatment of SS.

Keywords: CD4(+) T cells; CD8(+) T cells; EZH2; GSK343; Sjögren's syndrome.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Disease Models, Animal
  • Mice
  • Mice, Inbred NOD
  • Salivary Glands
  • Sjogren's Syndrome* / drug therapy
  • Submandibular Gland / metabolism
  • Submandibular Gland / pathology