期刊
IMMUNITY
卷 54, 期 6, 页码 1200-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2021.04.001
关键词
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类别
资金
- NIH [AI112844, AI147394, AG069264, AG047156, AI129241, AI067545]
- Mayo Clinic Kogod Aging Center and Center for Biomedical Discovery funds
This study revealed the important role of the Wnt/β-catenin pathway in regulating the proliferative and inflammatory properties of lung macrophages, with implications for the treatment of severe respiratory diseases.
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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