Inhibition of the endoplasmic reticulum (ER) stress-associated IRE-1/XBP-1 pathway alleviates acute lung injury via modulation of macrophage activation.

Content Provider	Europe PMC
Author	Zhao, Yanfeng Jiang, Yan Chen, Linsong Zheng, Xinlin Zhu, Junjie Song, Xiao Shi, Jinghan Li, Yuping He, Wenxin
Copyright Year	2020
Abstract	BackgroundBoth endoplasmic reticulum (ER) stress and macrophage diversity contribute to inflammatory processes in lung injury. However, the interaction between ER stress and macrophage M1/M2 imbalance in lung inflammation remains unclear. The present study, thus, aimed to evaluate the role of ER stress-mediated macrophage phenotype changes in lipopolysaccharide (LPS)-induced acute lung injury (ALI).MethodsLung inflammation and injury were examined in a murine model of LPS-induced ALI with or without ER stress inhibitors. Alveolar macrophage (AM) polarization was determined by flow cytometry. Bone marrow-derived macrophages (BMDMs) were treated with either an ER stress inducer, inhibitor, or an IRE-1 endonuclease inhibitor before being polarized to an M1 and M2 phenotype. The macrophage polarization status was examined via RT-PCR and flow cytometry.ResultsOur results indicated that ER stress and IRE-1/XBP-1 signaling are activated in LPS-induced ALI. Furthermore, we observed that AM polarizes to an inflammatory phenotype upon exposure to LPS in the induction phase and an anti-inflammatory phenotype in the resolution phase of lung inflammation. Inhibition of ER stress attenuated the pathophysiological features of LPS-induced lung inflammation/injury, as evidenced by a decrease in bronchoalveolar lavage (BAL) protein levels, the number of inflammatory cells, and the expression level of inflammatory mediators. In addition, the ER stress inducer promoted M1 polarization and the switch from M2 to M1 in BMDMs, whereas inhibition of ER stress and XBP-1 splicing suppressed M1 but did not promote M2, both in vivo and in vitro.ConclusionsOur results demonstrated that inhibition of the ER stress-associated IRE-1/XBP-1 signaling pathway suppresses M1 polarization and ameliorates LPS-induced lung injury. This indicates that the interaction between ER stress and macrophage polarization might be a novel therapeutic target for endotoxin-induced lung inflammatory disorders.
ISSN	20721439
Journal	Journal of Thoracic Disease
Volume Number	12
PubMed Central reference number	PMC7139036
Issue Number	3
PubMed reference number	32274095
e-ISSN	20776624
DOI	10.21037/jtd.2020.01.45
Language	English
Publisher	AME Publishing Company
Publisher Date	2020-03-01
Access Restriction	Open
Rights License	Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0. 2020 Journal of Thoracic Disease. All rights reserved.
Subject Keyword	Acute lung injury (ALI) endoplasmic reticulum stress (ER stress) inflammation lipopolysaccharide (LPS) macrophage polarization
Content Type	Text
Resource Type	Article
Subject	Pulmonary and Respiratory Medicine