BIG1 mediates sepsis-induced lung injury by modulating lipid raft-dependent macrophage inflammatory responses.

Minli Sun, Xiaodan Han, Di Zhou, Jing Zhong, Lixin Liu, Yirui Wang, Jiahui Ni, Xiaoyan Shen, Chao Liang, Hao Fang

Acta biochimica et biophysica Sinica 2021 Jul 28

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Sepsis is a systemic inflammatory response syndrome with high mortality. It has been reported that brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) is involved in the pathogenesis of sepsis. However, the mechanism is not fully elucidated. In the present study, we explored the role of BIG1 in mediating lipid raft-dependent macrophage inflammatory response and its impact on lung injury in murine sepsis. In vitro studies revealed that BIG1 deficiency reduces the upregulation and secretion of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1β and inhibits the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88-dependent nuclear factor kappa-B signaling pathway induced by the lipopolysaccharide (LPS) treatment. Further experiments revealed that the inhibitory effects of BIG1 deficiency on LPS-induced inflammation are due to the upregulation of adenosine triphosphate-binding cassette transporter A1. This promotes the free-cholesterol efflux from lipid rafts and results in the reduction of lipid raft TLR4 content. The decrease in TLR4 content in lipid raft thereby inhibits the LPS-induced inflammatory response. Furthermore, using the cecal ligation and puncture-induced polymicrobial sepsis mouse model, we found that conditional knockout (cKO) of the myeloid cell BIG1 significantly reduced the serum concentrations of TNF-α, IL-6, and IL-1β, and downregulated their mRNA expressions in the lungs. Pathological analysis confirmed that the BIG1 cKO alleviated the sepsis-induced lung injury. These results revealed the crucial new role of BIG1 in mediating lipid raft-dependent macrophage inflammatory response. Hence, BIG1 may be a potential promising therapeutic target for the treatment of septic lung injury. © The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Minli Sun, Xiaodan Han, Di Zhou, Jing Zhong, Lixin Liu, Yirui Wang, Jiahui Ni, Xiaoyan Shen, Chao Liang, Hao Fang. BIG1 mediates sepsis-induced lung injury by modulating lipid raft-dependent macrophage inflammatory responses. Acta biochimica et biophysica Sinica. 2021 Jul 28;53(8):1088-1097