Macrophages activated by hepatitis B virus have distinct metabolic profiles and suppress the virus via IL-1β to downregulate PPARα and FOXO3
Yumei Li,
Yanwen Zhu,
Shu Feng,
Yuji Ishida,
Tsu-Pei Chiu,
Takeshi Saito,
Sean Wang,
David K. Ann,
Jing-hsiung James Ou
Affiliations
Yumei Li
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Yanwen Zhu
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Shu Feng
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Yuji Ishida
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
Tsu-Pei Chiu
Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
Takeshi Saito
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
Sean Wang
Michael Amini Transfusion Medicine Center, City of Hope, Duarte, CA, USA
David K. Ann
Beckman Research Institute, City of Hope, Duarte, CA, USA
Jing-hsiung James Ou
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; Corresponding author
Summary: 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.
