GABA transporter sustains IL-1β production in macrophages

被引：74

作者：

Xia, Yaoyao ^{[1
]}

He, Fang ^{[2
]}

Wu, Xiaoyan ^{[1
]}

Tan, Bie ^{[3
]}

Chen, Siyuan ^{[1
]}

Liao, Yuexia ^{[4
]}

Qi, Ming ^{[5
]}

Chen, Shuai ^{[5
]}

Peng, Yuanyi ^{[2
]}

Yin, Yulong ^{[5
]}

Ren, Wenkai ^{[1
]}

机构：

[1] South China Agr Univ, Coll Anim Sci,Guangdong Lab Lingnan Modern Agr, Natl Engn Res Ctr Breeding Swine Ind, State Key Lab Conservat & Utilizat Subtrop Agrobi, Guangzhou, Peoples R China

[2] Southwest Univ, Coll Anim Sci & Technol, Chongqing 400715, Peoples R China

[3] Hunan Agr Univ, Coll Anim Sci & Technol, Changsha 410128, Peoples R China

[4] Yangzhou Univ, Coll Nursing, Yangzhou 225009, Jiangsu, Peoples R China

[5] Chinese Acad Sci, Inst Subtrop Agr, Changsha 410125, Peoples R China

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 15期

基金：

中国国家自然科学基金;

关键词：

NLRP3 INFLAMMASOME ACTIVATION; PHOSPHORYLATION; INHIBITION; METABOLISM; DNA;

D O I：

10.1126/sciadv.abe9274

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Accumulating evidence shows that nervous system governs host immune responses; however, how gamma-aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1 beta (IL-1 beta) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3-ASC-caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.

引用

页数：18

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