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/β-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of β-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, β-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 β-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This β-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by β-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.
Original language | English (US) |
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Pages (from-to) | 1200-1218.e9 |
Journal | Immunity |
Volume | 54 |
Issue number | 6 |
DOIs | |
State | Published - Jun 8 2021 |
Keywords
- HIF-1α
- SARS-CoV-2
- alveolar macrophages
- influenza virus
- pulmonary inflammation
- self-renewal
- tissue macrophages
- tissue repair
- β-catenin
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases