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

• DOI: 10.1172/jci.insight.120596
• Publication Date: 2018-10-03T15:01:24Z
• Authors: Min Zhang; Kojiro Nakamura; Shoichi Kageyama; Akeem O. Lawal; Ke Wei Gong; May Bhetraratana; Takehiro Fujii; Dawoud Sulaiman; Hirofumi Hirao; Subhashini Bolisetty; Jerzy W. Kupiec-W...; Jesus A. Araujo
• Keywords: Adult; Graft Rejection; Male; Biomedical and clinical sciences; Adolescent; Knockout; Biopsy; Clinical Sciences; 610; Young Adult; Mice; 03 medical and health sciences; Liver Function Tests; 2.1 Biological and endogenous factors; Animals; Humans; Inflammation; Innate immunity; Mice, Knockout; Transplantation; 0303 health sciences; Biomedical and Clinical Sciences; Hepatology; Animal; Liver Disease; Macrophages; Health sciences; Membrane Proteins; Organ Transplantation; Middle Aged; Allografts; Liver Transplantation; 3. Good health; Disease Models, Animal; Liver; Reperfusion Injury; Disease Models; Female; Digestive Diseases; Heme Oxygenase-1; Signal Transduction

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.