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Article: The IL‐21‐TET2‐AIM2‐c‐MAF pathway drives the T follicular helper cell response in lupus‐like disease

TitleThe IL‐21‐TET2‐AIM2‐c‐MAF pathway drives the T follicular helper cell response in lupus‐like disease
Authors
Issue Date1-Mar-2022
PublisherWiley Open Access
Citation
Clinical and Translational Medicine, 2022, v. 12, n. 3 How to Cite?
Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that involves T follicular helper (T-FH) cell-mediated humoral immune responses. Absent in melanoma 2 (human AIM2 and murine Aim2) is a well-known component of the inflammasome in the innate immune system. Surprisingly, we observed that in SLE patients, upregulated levels of AIM2 expression were found in peripheral blood and skin lesions, with the highest levels detected in T-FH-like cells. In the CD4(cre)Aim2(fl/fl) conditional knockout mice, a markedly reduced T-FH cell response was observed, with significantly lower levels of serum autoantibodies and proteinuria, as well as profoundly reduced renal IgG deposition in pristane-induced lupus mice. Mechanistically, IL-21 was found to recruit hydroxymethyltransferase ten-eleven translocation 2 (TET2) to the AIM2 promoter, resulting in DNA demethylation and increased transcription of AIM2. In addition, AIM2 could regulate c-MAF expression to enhance IL-21 production, which consequently promoted T-FH cell differentiation. Our results have identified a role of AIM2 in promoting the T-FH cell response and further revealed that the IL-21-TET2-AIM2-c-MAF signalling pathway is dysregulated in lupus pathogenesis, which provides a potential therapeutic target for SLE.


Persistent Identifierhttp://hdl.handle.net/10722/331776
ISSN
2023 Impact Factor: 7.9
2023 SCImago Journal Rankings: 2.424

 

DC FieldValueLanguage
dc.contributor.authorWu, Haijing-
dc.contributor.authorDeng, Yaxiong-
dc.contributor.authorLong, Di-
dc.contributor.authorYang, Ming-
dc.contributor.authorLi, Qianwen-
dc.contributor.authorFeng, Yu-
dc.contributor.authorChen, Yongjian-
dc.contributor.authorQiu, Hong-
dc.contributor.authorHuang, Xin-
dc.contributor.authorHe, Zhenghao-
dc.contributor.authorHu, Longyuan-
dc.contributor.authorYin, Heng-
dc.contributor.authorLi, Guangdi-
dc.contributor.authorGuo, Yunkai-
dc.contributor.authorDu, Wenhan-
dc.contributor.authorZhao, Ming-
dc.contributor.authorLu, Liwei-
dc.contributor.authorLu, Qianjin-
dc.date.accessioned2023-09-21T06:58:48Z-
dc.date.available2023-09-21T06:58:48Z-
dc.date.issued2022-03-01-
dc.identifier.citationClinical and Translational Medicine, 2022, v. 12, n. 3-
dc.identifier.issn2001-1326-
dc.identifier.urihttp://hdl.handle.net/10722/331776-
dc.description.abstract<p>Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that involves T follicular helper (T-FH) cell-mediated humoral immune responses. Absent in melanoma 2 (human AIM2 and murine Aim2) is a well-known component of the inflammasome in the innate immune system. Surprisingly, we observed that in SLE patients, upregulated levels of AIM2 expression were found in peripheral blood and skin lesions, with the highest levels detected in T-FH-like cells. In the CD4(cre)Aim2(fl/fl) conditional knockout mice, a markedly reduced T-FH cell response was observed, with significantly lower levels of serum autoantibodies and proteinuria, as well as profoundly reduced renal IgG deposition in pristane-induced lupus mice. Mechanistically, IL-21 was found to recruit hydroxymethyltransferase ten-eleven translocation 2 (TET2) to the AIM2 promoter, resulting in DNA demethylation and increased transcription of AIM2. In addition, AIM2 could regulate c-MAF expression to enhance IL-21 production, which consequently promoted T-FH cell differentiation. Our results have identified a role of AIM2 in promoting the T-FH cell response and further revealed that the IL-21-TET2-AIM2-c-MAF signalling pathway is dysregulated in lupus pathogenesis, which provides a potential therapeutic target for SLE.<br></p>-
dc.languageeng-
dc.publisherWiley Open Access-
dc.relation.ispartofClinical and Translational Medicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleThe IL‐21‐TET2‐AIM2‐c‐MAF pathway drives the T follicular helper cell response in lupus‐like disease-
dc.typeArticle-
dc.identifier.doi10.1002/ctm2.781-
dc.identifier.volume12-
dc.identifier.issue3-
dc.identifier.eissn2001-1326-
dc.identifier.issnl2001-1326-

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