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

Bibo Zhu, Yue Wu, Su Huang, Ruixuan Zhang, Young Min Son, Chaofan Li, In Su Cheon, Xiaochen Gao, Min Wang, Yao Chen, Xian Zhou, Quynh Nguyen, Anthony T. Phan, Supriya Behl, M. Mark Taketo, Matthias Mack, Virginia S. Shapiro, Hu Zeng, Hideki Ebihara, John J. MullonEric S. Edell, Janani S. Reisenauer, Nadir Demirel, Ryan M. Kern, Rana Chakraborty, Weiguo Cui, Mark H. Kaplan, Xiaobo Zhou, Ananda W. Goldrath, Jie Sun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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 languageEnglish (US)
Pages (from-to)1200-1218.e9
Issue number6
StatePublished - Jun 8 2021


  • 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


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