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

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. Graphical abstract Zhu et al. examine the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt-β-catenin pathway, a regulator of self-renewal, in alveolar macrophages (AMs). Their findings reveal a β-catenin-HIF-1α signaling axis that promotes inflammatory AMs at the expense of proliferation. This axis is conserved in human AMs, with implications for the treatment of severe respiratory diseases.