title: Heme oxygenase-2 deletion impairs macrophage function: implication in wound healing.
abstract: Heme oxygenase (HO)-2 deficiency impairs wound healing and exacerbates inflammation following injury. We examine the impact of HO-2 deficiency on macrophage function and the contribution of macrophage HO-2 to inflammatory and repair responses to injury. Corneal epithelial debridement was performed in control and macrophage-depleted HO-2(-/-) and wild-type (WT) mice and in bone marrow chimeras. Peritoneal macrophages were collected for determination of phagocytic activity and classically activated macrophage (M1)-alternatively activated macrophage (M2) polarization. Depletion of macrophages delayed corneal healing (13.2%) and increased neutrophil infiltration (54.1%) by day 4 in WT mice, whereas in HO-2(-/-) mice, it did not worsen the already impaired wound healing and exacerbated inflammation. HO-2(-/-) macrophages displayed an altered M1 phenotype with no significant expression of M2 or M2-like activated cells and a 31.3% reduction in phagocytic capacity that was restored by inducing HO-1 activity or supplementing biliverdin. Macrophage depletion had no effect, whereas adoptive transfer of WT bone marrow improved wound healing (34% on day 4) but did not resolve the exaggerated inflammatory response in HO-2(-/-) mice. These findings indicate that HO-2-deficient macrophages are dysfunctional and that macrophage HO-2 is required for proper macrophage function but is insufficient to correct the impaired healing of the HO-2(-/-) cornea, suggesting that corneal epithelial expression of HO-2 is a key to resolution and repair in wound healing.
authors.affiliation: Department of Pharmacology, lars_bellner@nymc.edu.
authors.forename: Lars
authors.initials: L
authors.lastname: Bellner
authors.affiliation: Department of Pharmacology.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Marrazzo
authors.affiliation: Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: Department of Ophthalmology, and.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Dunn
authors.affiliation: Department of Pharmacology, Department of Medicine, New York Medical College, Valhalla, New York, USA; and.
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.affiliation: Department of Pharmacology, Department of Ophthalmology, and.
authors.forename: Michal L
authors.initials: ML
authors.lastname: Schwartzman
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D065306:Corneal Injuries / Q000473:pathology / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis; D019573:Epithelium, Corneal / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency* / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000502:physiology; D010587:Phagocytosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018183:Transplantation Chimera / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2
keywords: bone marrow transfer; clodronate liposomes; inflammation