Macrophages activated by hepatitis B virus have distinct metabolic profiles and suppress the virus via IL-1β to downregulate PPARα and FOXO3

  • Cell Rep. 2022 Jan 25;38(4):110284. doi: 10.1016/j.celrep.2021.110284.
Yumei Li  1 ,  Yanwen Zhu  1 ,  Shu Feng  1 ,  Yuji Ishida  2 ,  Tsu-Pei Chiu  3 ,  Takeshi Saito  4 ,  Sean Wang  5 ,  David K Ann  6 ,  Jing-Hsiung James Ou  7
Affiliations
  • 1. Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
  • 2. Department of Medicine, Division of Gastrointestinal and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; PhoenixBio, Kagamiyama, Higashi-Hiroshima, Hiroshima, Japan.
  • 3. Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.
  • 4. Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; Department of Medicine, Division of Gastrointestinal and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
  • 5. Michael Amini Transfusion Medicine Center, City of Hope, Duarte, CA, USA.
  • 6. Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 7. Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. Electronic address: [email protected].
PMID: 35081341 DOI: 10.1016/j.celrep.2021.110284
Abstract

Macrophages display phenotypic plasticity and can be induced by hepatitis B virus (HBV) to undergo either M1-like pro-inflammatory or M2-like anti-inflammatory polarization. Here, we report that M1-like macrophages stimulated by HBV exhibit a strong HBV-suppressive effect, which is diminished in M2-like macrophages. Transcriptomic analysis reveals that HBV induces the expression of interleukin-1β (IL-1β) in M1-like macrophages, which display a high Oxidative Phosphorylation (OXPHOS) activity distinct from that of conventional M1-like macrophages. Further analysis indicates that OXPHOS attenuates the expression of IL-1β, which suppresses the expression of Peroxisome Proliferator-activated Receptor α (PPARα) and forkhead box O3 (FOXO3) in hepatocytes to suppress HBV gene expression and replication. Moreover, multiple HBV proteins can induce the expression of IL-1β in macrophages. Our results thus indicate that macrophages can respond to HBV by producing IL-1β to suppress HBV replication. However, HBV can also metabolically reprogram macrophages to enhance OXPHOS to minimize this host Antiviral response.

Keywords
IL-1β signaling; M1-like and M2-like macrophages; hepatitis B virus; metabolic reprogramming; oxidative phosphorylation; transcriptional regulation.
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