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: Francesca Vinchi, Milene Costa da Silva, Giada Ingoglia, Sara Petrillo, Nathan Brinkman, Adrian Zuercher, Adelheid Cerwenka, Emanuela Tolosano, Martina U Muckenthaler
• Journal: Blood (Blood) Vol. 127 Issue 4 Pg. 473-86 (Jan 28 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 26675351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Reactive Oxygen Species
• Toll-Like Receptor 4
• Heme
• Hemopexin

Topics

• Anemia, Sickle Cell (drug therapy, genetics, immunology, pathology)
• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Cell Line
• Cells, Cultured
• Cytokines (immunology)
• Disease Models, Animal
• Gene Deletion
• Heme (immunology)
• Hemopexin (genetics, therapeutic use)
• Humans
• Macrophages (drug effects, immunology, pathology)
• Mice
• Mice, Knockout
• Reactive Oxygen Species (immunology)
• Toll-Like Receptor 4 (immunology)