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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury.

Authors: Zhang, Min; Nakamura, Kojiro; Kageyama, Shoichi; Lawal, Akeem O; Gong, Ke Wei; Bhetraratana, May; Fujii, Takehiro; Sulaiman, Dawoud; Hirao, Hirofumi; Bolisetty, Subhashini; Kupiec-Weglinski, Jerzy W; Araujo, Jesus A

Published In JCI Insight, (2018 10 04)

Abstract: Macrophages polarize into heterogeneous proinflammatory M1 and antiinflammatory M2 subtypes. Heme oxygenase 1 (HO-1) protects against inflammatory processes such as ischemia-reperfusion injury (IRI), organ transplantation, and atherosclerosis. To test our hypothesis that HO-1 regulates macrophage polarization and protects against IRI, we generated myeloid-specific HO-1-knockout (mHO-1-KO) and -transgenic (mHO-1-Tg) mice, with deletion or overexpression of HO-1, in various macrophage populations. Bone marrow-derived macrophages (BMDMs) from mHO-1-KO mice, treated with M1-inducing LPS or M2-inducing IL-4, exhibited increased mRNA expression of M1 (CXCL10, IL-1β, MCP1) and decreased expression of M2 (Arg1 and CD163) markers as compared with controls, while BMDMs from mHO-1-Tg mice displayed the opposite. A similar pattern was observed in the hepatic M1/M2 expression profile in a mouse model of liver IRI. mHO-1-KO mice displayed increased hepatocellular damage, serum AST/ALT levels, Suzuki's histological score of liver IRI, and neutrophil and macrophage infiltration, while mHO-1-Tg mice exhibited the opposite. In human liver transplant biopsies, subjects with higher HO-1 levels showed lower expression of M1 markers together with decreased hepatocellular damage and improved outcomes. In conclusion, myeloid HO-1 expression modulates macrophage polarization, and protects against liver IRI, at least in part by favoring an M2 phenotype.

PubMed ID: 30282830 Exiting the NIEHS site

MeSH Terms: Adolescent; Adult; Allografts/blood supply; Allografts/cytology; Allografts/pathology; Animals; Biopsy; Disease Models, Animal; Female; Graft Rejection/diagnosis; Graft Rejection/immunology*; Graft Rejection/pathology; Heme Oxygenase-1/genetics; Heme Oxygenase-1/metabolism*; Humans; Liver Function Tests; Liver Transplantation/adverse effects*; Liver/blood supply; Liver/cytology; Liver/pathology; Macrophages/immunology*; Macrophages/metabolism; Male; Membrane Proteins/genetics; Membrane Proteins/metabolism*; Mice; Mice, Knockout; Middle Aged; Reperfusion Injury/diagnosis; Reperfusion Injury/immunology*; Reperfusion Injury/pathology; Signal Transduction/immunology; Young Adult

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