Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infectionopen access
- Authors
- Zhu, Bibo; Wu, Yue; Huang, Su; Zhang, Ruixuan; Son, Young Min; Li, Chaofan; Cheon, In Su; Gao, Xiaochen; Wang, Min; Chen, Yao; Zhou, Xian; Quynh Nguyen; Phan, Anthony T.; Behl, Supriya; Taketo, M. Mark; Mack, Matthias; Shapiro, Virginia S.; Zeng, Hu; Ebihara, Hideki; Mullon, John J.; Edell, Eric S.; Reisenauer, Janani S.; Demirel, Nadir; Kern, Ryan M.; Chakraborty, Rana; Cui, Weiguo; Kaplan, Mark H.; Zhou, Xiaobo; Goldrath, 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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