Author:
Li Xianjing,Wang Duowei,Chen Zhen,Lu Ermei,Wang Zhuo,Duan Jingjing,Tian Wei,Wang Yun,You Linjun,Zou Yulian,Cheng Yan,Zhu Qingyi,Wan Xiaojian,Xi Tao,Jiang Meisheng,Han Yuyuan,Cao Cong,Birnbaumer Lutz,Chu Wen-Ming,Yang Yong
Abstract
Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gαi1/3) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gαi1/3form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gαi1/3deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gαi1/3knockdown in bone marrow-derived macrophage cells (Gαi1/3KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Gαi1/3deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gαi1/3were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gαi1/3can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.
Funder
HHS | National Institutes of Health
National Science Foundation of China
National Natural Science Foundation of Jiangsu Province
Publisher
Proceedings of the National Academy of Sciences
Cited by
40 articles.
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