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Cigarette smoke induces endoplasmic reticulum stress and suppresses efferocytosis through the activation of RhoA

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Title: Cigarette smoke induces endoplasmic reticulum stress and suppresses efferocytosis through the activation of RhoA
Authors: Ito, Hiroyuki / Yamashita, Yoshiro / Tanaka, Takeshi / Takaki, Masahiro / Le, Minh Nhat / Yoshida, Lay-Myint / Morimoto, Konosuke
Issue Date: 28-Jul-2020
Publisher: Nature Research
Citation: Scientific Reports, 10(1), art.no.12620; 2020
Abstract: Impaired efferocytosis is a key mechanism of inflammatory lung diseases, including chronic obstructive pulmonary disease and cystic fibrosis.Cigarette smoking activates RhoA and impairs efferocytosis in alveolar macrophages, but the mechanism has not been fully elucidated. We investigated the role of endoplasmic reticulum (ER) stress induced by cigarette smoking in the disruption of efferocytosis.Both tunicamycin (10 μg/ml) and thapsigargin (0.1 and 1 μM), which are ER stress inducers, suppressed efferocytosis in J774 cells,and a Rho-associated coiled-coil-forming kinase (ROCK) inhibitor (Y27632) reversed this effect.We validated the effect of tunicamycin on efferocytosis in experiments using RAW264.7 cells. Then, we investigated the role of the unfolded protein response (UPR) in efferocytosis impaired by ER stress. A PERK inhibitor (GSK2606414) restored the efferocytosis that had been impaired by TM, and an eIF2α dephosphorylation inhibitor (salubrinal) suppressed efferocytosis. Cigarette smoke extract (CSE) induced ER stress in J774 macrophages and RhoA activation in J774 cells, and the CSE-induced ROCK activity was successfully reversed by GSK2606414 and tauroursodeoxycholic acid. Finally, we confirmed that ER stress suppresses efferocytosis in murine alveolar macrophages and that GSK2606414 could rescue this process. These data suggest that cigarette smoke-induced ER stress and the UPR play crucial roles in RhoA activation and suppression of efferocytosis in the lung.
URI: http://hdl.handle.net/10069/40206
DOI: 10.1038/s41598-020-69610-x
Rights: © 2020, The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/40206

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