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Article: GITRL impairs the immunosuppressive function of MDSCs via PTEN-mediated signaling pathway in experimental Sjögren syndrome

TitleGITRL impairs the immunosuppressive function of MDSCs via PTEN-mediated signaling pathway in experimental Sjögren syndrome
Authors
KeywordsAutoimmune disease
GITRL
MDSCs
PTEN
Sjögren’s syndrome
Issue Date27-Oct-2022
PublisherSpringer
Citation
Inflammation Research, 2022, v. 71 How to Cite?
Abstract

Background Recent studies have revealed a role of the ligand for glucocorticoid-induced TNFR family-related protein (GITRL) in mediating functional dysregulations of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of primary Sjogren syndrome (pSS), but the underlying molecular mechanism is largely unclear. In this study, we aimed to elucidate GITRL-mediated signaling pathways in MDSCs during the development of experimental SS (ESS). Methods MDSCs were stimulated with recombinant GITRL, the activation of PTEN, AKT and STAT3 in MDSCs was analyzed by Western blot. MDSCs with different treatment were adoptively transferred to ESS mice. ELISA was used to detect the level of autoantibodies. Proportions of Th1 and Th17 cells were examined by flow cytometry. Histological evaluation of glandular destruction was analyzed by hematoxylin and eosin (HE) staining. The interaction of GITR, TRAF3 and PP2A was detected by CoIP. Results Upon the engagement of GITR on MDSCs, PTEN was activated and led to the inhibition of downstream AKT/STAT3 signaling pathway, therefore, resulting in the impaired immunosuppressive function of MDSCs. In ESS mice, blocking the activity of PTEN could efficiently restore the immunomodulatory effect of MDSCs and alleviate the progression of ESS. Furthermore, TRAF3 was found to bind to GITR, and then recruited PP2A to dephosphorylate PTEN, thus enhancing the activity of PTEN. Conclusion This study elucidated the molecular mechanism underlying the effect of GITRL in regulating the function of MDSCs, which may provide a new therapeutic target for the treatment of pSS.


Persistent Identifierhttp://hdl.handle.net/10722/331728
ISSN
2023 Impact Factor: 4.8
2023 SCImago Journal Rankings: 1.309
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTian, Jie-
dc.contributor.authorZhang, Beibei-
dc.contributor.authorYuan, Qingfang-
dc.contributor.authorSun, Xueqing-
dc.contributor.authorPeng, Na-
dc.contributor.authorZhu, Bo-
dc.contributor.authorLiu, Chang-
dc.contributor.authorWang, Xiaoran-
dc.contributor.authorHan, Man-
dc.contributor.authorCao, Meng-
dc.contributor.authorXiao, Fan-
dc.contributor.authorWang, Shengjun-
dc.contributor.authorRui, Ke-
dc.contributor.authorLu, Liwei-
dc.date.accessioned2023-09-21T06:58:23Z-
dc.date.available2023-09-21T06:58:23Z-
dc.date.issued2022-10-27-
dc.identifier.citationInflammation Research, 2022, v. 71-
dc.identifier.issn1023-3830-
dc.identifier.urihttp://hdl.handle.net/10722/331728-
dc.description.abstract<p>Background Recent studies have revealed a role of the ligand for glucocorticoid-induced TNFR family-related protein (GITRL) in mediating functional dysregulations of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of primary Sjogren syndrome (pSS), but the underlying molecular mechanism is largely unclear. In this study, we aimed to elucidate GITRL-mediated signaling pathways in MDSCs during the development of experimental SS (ESS). Methods MDSCs were stimulated with recombinant GITRL, the activation of PTEN, AKT and STAT3 in MDSCs was analyzed by Western blot. MDSCs with different treatment were adoptively transferred to ESS mice. ELISA was used to detect the level of autoantibodies. Proportions of Th1 and Th17 cells were examined by flow cytometry. Histological evaluation of glandular destruction was analyzed by hematoxylin and eosin (HE) staining. The interaction of GITR, TRAF3 and PP2A was detected by CoIP. Results Upon the engagement of GITR on MDSCs, PTEN was activated and led to the inhibition of downstream AKT/STAT3 signaling pathway, therefore, resulting in the impaired immunosuppressive function of MDSCs. In ESS mice, blocking the activity of PTEN could efficiently restore the immunomodulatory effect of MDSCs and alleviate the progression of ESS. Furthermore, TRAF3 was found to bind to GITR, and then recruited PP2A to dephosphorylate PTEN, thus enhancing the activity of PTEN. Conclusion This study elucidated the molecular mechanism underlying the effect of GITRL in regulating the function of MDSCs, which may provide a new therapeutic target for the treatment of pSS.<br></p>-
dc.languageeng-
dc.publisherSpringer-
dc.relation.ispartofInflammation Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAutoimmune disease-
dc.subjectGITRL-
dc.subjectMDSCs-
dc.subjectPTEN-
dc.subjectSjögren’s syndrome-
dc.titleGITRL impairs the immunosuppressive function of MDSCs via PTEN-mediated signaling pathway in experimental Sjögren syndrome-
dc.typeArticle-
dc.identifier.doi10.1007/s00011-022-01660-5-
dc.identifier.scopuseid_2-s2.0-85140580469-
dc.identifier.volume71-
dc.identifier.eissn1420-908X-
dc.identifier.isiWOS:000874400800001-
dc.identifier.issnl1023-3830-

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