High salt promotes autoimmunity by TET2-induced DNA demethylation and driving the differentiation of Tfh cells.
Follicular helper T cells (Tfh) have been well documented to play a critical role in autoimmunity, such as systemic lupus erythematosus (SLE), by helping B cells. In this study, high salt (sodium chloride, NaCl), under physiological conditions, was demonstrated to increase the differentiation of Tfh. A high-salt diet markedly increased lupus features in MRL/lpr mice. The mechanism is NaCl-induced DNA demethylation via the recruitment of the hydroxytransferase Ten-Eleven Translocation 2 (TET2). Gene silencing of TET2 obviously diminished NaCl-induced Tfh cell polarization in vitro. In addition, the gene expression of sh2d1a, map3k1, spn and stat5b was enhanced after NaCl treatment, consistent with the findings in lupus CD4(+)T cells. However, only spn was directly regulated by TET2, and spn was not the sole target for NaCl. Our findings not only explain the epigenetic mechanisms of high-salt induced autoimmunity but also provide an attractive molecular target for intervention strategies of patients.
Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Haijing
H
Wu
Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Xin
X
Huang
Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Hong
H
Qiu
Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Ming
M
Zhao
Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Wei
W
Liao
Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Shuguang
S
Yuan
Changsha Blood Center, Changsha, Hunan, China.
Yubing
Y
Xie
Clinical medical research center, the Second Clinical medical college of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong, China.
Yong
Y
Dai
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, USA.
Christopher
C
Chang
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
Akihiko
A
Yoshimura
Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Qianjin
Q
Lu
D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D000073399:DNA Demethylation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D015996:Survival Rate; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D017673:Sodium Chloride, Dietary; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D048728:MAP Kinase Kinase Kinase 1