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Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infectionopen access

Authors
Zhu, BiboWu, YueHuang, SuZhang, RuixuanSon, Young MinLi, ChaofanCheon, In SuGao, XiaochenWang, MinChen, YaoZhou, XianQuynh NguyenPhan, Anthony T.Behl, SupriyaTaketo, M. MarkMack, MatthiasShapiro, Virginia S.Zeng, HuEbihara, HidekiMullon, John J.Edell, Eric S.Reisenauer, Janani S.Demirel, NadirKern, Ryan M.Chakraborty, RanaCui, WeiguoKaplan, Mark H.Zhou, XiaoboGoldrath, Ananda W.Sun, Jie
Issue Date
Jun-2021
Publisher
CELL PRESS
Keywords
alveolar macrophages; HIF-1α; influenza virus; pulmonary inflammation; SARS-CoV-2; self-renewal; tissue macrophages; tissue repair; β-catenin
Citation
IMMUNITY, v.54, no.6, pp 1200 - +
Journal Title
IMMUNITY
Volume
54
Number
6
Start Page
1200
End Page
+
URI
https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/72079
DOI
10.1016/j.immuni.2021.04.001
ISSN
1074-7613
1097-4180
Abstract
Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/beta-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of beta-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, beta-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted beta-catenin-HIF-1 alpha interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1 alpha activities distinguished proliferative and inflammatory AMs in vivo. This beta-catenin-HIF-1 alpha axis was conserved in human AMs and enhanced HIF-1 alpha expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by beta-catenin-HIF-1 alpha signaling, with implications for the treatment of severe respiratory diseases.
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Son, Young Min
생명공학대학 (시스템생명공학과)
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