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

Immunity. 2021 Jun 8;54(6):1200-1218.e9. doi: 10.1016/j.immuni.2021.04.001. Epub 2021 May 4.


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.

Keywords: HIF-1α; SARS-CoV-2; alveolar macrophages; influenza virus; pulmonary inflammation; self-renewal; tissue macrophages; tissue repair; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers
  • COVID-19 / immunology*
  • COVID-19 / metabolism
  • COVID-19 / virology*
  • Cell Self Renewal / immunology*
  • Cytokines / metabolism
  • Disease Susceptibility / immunology
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inflammation Mediators / metabolism
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • SARS-CoV-2 / immunology*
  • Signal Transduction


  • Biomarkers
  • Cytokines
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inflammation Mediators