Uncoupling of macrophage inflammation from self-renewal modulates host recovery from respiratory viral infection.
Immunity
; 54(6): 1200-1218.e9, 2021 06 08.
Article
in English
| MEDLINE | ID: covidwho-1213288
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/ß-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of ß-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, ß-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 ß-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 ß-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 ß-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Host-Pathogen Interactions
/
Cell Self Renewal
/
SARS-CoV-2
/
COVID-19
/
Macrophages
Type of study:
Prognostic study
Limits:
Humans
Language:
English
Journal:
Immunity
Journal subject:
Allergy and Immunology
Year:
2021
Document Type:
Article
Affiliation country:
J.immuni.2021.04.001
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