title: Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease.
abstract: Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages, and chronic inflammation. Here we show that in addition to activating the vascular endothelium, hemoglobin and heme excess alters the macrophage phenotype in sickle cell disease. We demonstrate that exposure of cultured macrophages to hemolytic aged red blood cells, heme, or iron causes their functional phenotypic change toward a proinflammatory state. In addition, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle disease trigger similar proinflammatory phenotypic alterations in hepatic macrophages. On the mechanistic level, this critically depends on reactive oxygen species production and activation of the Toll-like receptor 4 signaling pathway. We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice and reduces production of cytokines and reactive oxygen species. Importantly, in sickle mice, the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages. Taken together, our data suggest that therapeutic administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation and its pathophysiologic consequences in sickle cell disease.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg University & European Molecular Biology Laboratory, Heidelberg, Germany; Molecular Biotechnology Center & Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Vinchi
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg University & European Molecular Biology Laboratory, Heidelberg, Germany; Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal; Innate Immunity Group, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Milene
authors.initials: M
authors.lastname: Costa da Silva
authors.affiliation: Molecular Biotechnology Center & Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy;
authors.forename: Giada
authors.initials: G
authors.lastname: Ingoglia
authors.affiliation: Molecular Biotechnology Center & Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Petrillo
authors.affiliation: CSL Behring, Research & Development, Kankakee, IL; and.
authors.forename: Nathan
authors.initials: N
authors.lastname: Brinkman
authors.affiliation: CSL Behring, Research & Development, Bern, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Zuercher
authors.affiliation: Innate Immunity Group, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Adelheid
authors.initials: A
authors.lastname: Cerwenka
authors.affiliation: Molecular Biotechnology Center & Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy;
authors.forename: Emanuela
authors.initials: E
authors.lastname: Tolosano
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit, Heidelberg University & European Molecular Biology Laboratory, Heidelberg, Germany;
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006418:Heme / Q000276:immunology*; D006466:Hemopexin / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; D006418:Heme; D006466:Hemopexin