title: Adoptive transfer of heme oxygenase-1 (HO-1)-modified macrophages rescues the nuclear factor erythroid 2-related factor (Nrf2) antiinflammatory phenotype in liver ischemia/reperfusion injury.
abstract: Macrophages are instrumental in the pathophysiology of liver ischemia/reperfusion injury (IRI). Although Nrf2 regulates macrophage-specific heme oxygenase-1 (HO-1) antioxidant defense, it remains unknown whether HO-1 induction might rescue macrophage Nrf2-dependent antiinflammatory functions. This study explores the mechanisms by which the Nrf2-HO-1 axis regulates sterile hepatic inflammation responses after adoptive transfer of ex vivo modified HO-1 overexpressing bone marrow-derived macrophages (BMMs). Livers in Nrf2-deficient mice preconditioned with Ad-HO-1 BMMs, but not Ad-β-Gal-BMMs, ameliorated liver IRI (at 6 h of reperfusion after 90 min of warm ischemia), evidenced by improved hepatocellular function (serum alanine aminotransferase [sALT] levels) and preserved hepatic architecture (Suzuki histological score). Treatment with Ad-HO-1 BMMs decreased neutrophil accumulation, proinflammatory mediators and hepatocellular necrosis/apoptosis in ischemic livers. Moreover, Ad-HO-1 transfection of Nrf2-deficient BMMs suppressed M1 (Nos2(+)) while promoting the M2 (Mrc-1/Arg-1(+)) phenotype. Unlike in controls, Ad-HO-1 BMMs increased the expression of Notch1, Hes1, phosphorylation of Stat3 and Akt in IR-stressed Nrf2-deficient livers as well as in lipopolysaccharide (LPS)-stimulated BMMs. Thus, adoptive transfer of ex vivo generated Ad-HO-1 BMMs rescued Nrf2-dependent antiinflammatory phenotype by promoting Notch1/Hes1/Stat3 signaling and reprogramming macrophages toward the M2 phenotype. These findings provide the rationale for a novel clinically attractive strategy to manage IR liver inflammation/damage.
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Xiu-Da
authors.initials: XD
authors.lastname: Shen
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Shi
authors.initials: S
authors.lastname: Yue
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Bibo
authors.initials: B
authors.lastname: Ke
authors.affiliation: Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000628:therapy*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D051881:Receptor, Notch1 / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000628:therapy*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051547:Heme Oxygenase-1; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D051881:Receptor, Notch1; D050796:STAT3 Transcription Factor; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C495636:Nfe2l2 protein, mouse; C497762:Notch1 protein, mouse; C494087:Stat3 protein, mouse; C496542:Hmox1 protein, mouse