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  2. Activation of TREM-1 induces endoplasmic reticulum stress through IRE-1α/XBP-1s pathway in murine macrophages

Activation of TREM-1 induces endoplasmic reticulum stress through IRE-1α/XBP-1s pathway in murine macrophages

  • Mol Immunol. 2021 Jul;135:294-303. doi: 10.1016/j.molimm.2021.04.023.
Liang Dong 1 Cheng-Wei Tan 2 Peng-Jiu Feng 3 Fu-Bing Liu 1 De-Xing Liu 1 Jun-Jie Zhou 2 Yan Chen 2 Xin-Xin Yang 2 Yu-Hang Zhu 4 Zhao-Qiong Zhu 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China.
  • 2 Graduate School, Zunyi Medical University, Zunyi, Guizhou, 563000, China.
  • 3 Department of Anesthesiology, The Third Affiliated Hospital, Guangxi University of Chinese Medicine, Liuzhou, Guangxi, 545001, China.
  • 4 Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China. Electronic address: zhuyuhang_zmc@sina.com.
  • 5 Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, China. Electronic address: zhuzhaoqiong@163.com.
Abstract

Increasing evidence suggests that endoplasmic reticulum (ER) stress activates several pro-inflammatory signaling pathways in many diseases, including acute lung injury (ALI). We have reported that blocking triggering receptor expressed on myeloid cells 1 (TREM-1) protects against ALI by suppressing pulmonary inflammation in mice with ALI induced by lipopolysaccharides (LPS). However, the molecular mechanism underlying the TREM-1-induced pro-inflammatory microenvironment in macrophages remains unclearly. Herein, we aimed to determine whether TREM-1 regulates the inflammatory responses induced by LPS associated with ER stress activation. We found that the activation of TREM-1 by a monoclonal agonist antibody (anti-TREM-1) increased the mRNA and protein levels of IL-1β, TNF-α, and IL-6 in primary macrophages. Treatment of the anti-TREM-1 antibody increased the expression of ER stress markers (ATF6, PERK, IRE-1α, and XBP-1s) in primary macrophages. While pretreatment with 4-PBA, an inhibitor of ER stress, significantly inhibited the expression of ER stress markers and pro-inflammatory cytokines and reduced LDH release. Furthermore, inhibiting the activity of the IRE-1α/XBP-1s pathway by STF-083010 significantly mitigated the increased levels of IL-1β, TNF-α, and IL-6 in macrophages treated by the anti-TREM-1 antibody. XBP-1 silencing attenuated pro-inflammatory microenvironment evoked by activation of TREM-1. Besides, we found that blockade of TREM-1 with LR12 ameliorated ER stress induced by LPS in vitro and in vivo. In conclusion, we conclude that TREM-1 activation induces ER stress through the IRE-1α/XBP-1s pathway in macrophages, contributing to the pro-inflammatory microenvironment.

Keywords

Endoplasmic reticulum stress; IRE-1α; Macrophages; TREM-1; XBP-1s.

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