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Heme Oxygenase 1 Directs Stress-Induced Remodeling of Iron-Recycling Macrophages

Fillebeen, Carine; Garcia-Santos, Daniel; Gkouvatsos, Konstantinos; Noushin, Saljoughian; Leroux, Louis-Philippe; Jaramillo, Maritza; Haliotis, Tina; Buffler, Marzel; Becker, Christiane; Schumann, Klaus; Ponka, Prem; Pantopoulos, Kostas (2017). Heme Oxygenase 1 Directs Stress-Induced Remodeling of Iron-Recycling Macrophages In: Seventh Congress of the International BioIron Society (IBIS): Biennial World Meeting (BioIron 2017), May 7 – 11, 2017, Los Angeles, USA.

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Résumé

Macrophages regulate systemic iron balance by recycling heme iron from senescent erythrocytes via heme oxygenase 1 (HO-1). We generated Hmox1LysM-Cre mice to explore implications of myeloid-specific HO-1 disruption in iron homeostasis. Bone marrow-derived or thioglycollate-elicited peritoneal Hmox1LysM-Cre macrophages lack any considerable HO-1 expression, which correlates with a prolonged pro-inflammatory phenotype and decreased viability following in vitro erythrophagocytosis. Hmox1LysM-Cre mice do not develop anemia, but manifest progressive splenomegaly, disruption of splenic architecture and proliferation of cells from the white pulp B cell areas. Despite an early delay in clearance of injected 59Fe-labeled erythrocytes from the blood, Hmox1LysM-Cre mice maintain physiological iron recycling by partially shifting heme catabolism from the liver to the spleen. Importantly, 59Fe-heme degradation occurs predominantly in the liver of control Hmox1fl/fl animals, and the contribution of the spleen is low. Consistently with these findings, Hmox1LysM-Cremice exhibit profound HO-1 ablation in Kupffer cells but retain considerable HO-1 expression in splenic and bone marrow macrophages. Hmox1LysM-Cre mice respond to phenylhydrazine-induced hemolysis by recruiting HO-1-expressing macrophages from the bone marrow to the liver, and by inducing residual HO-1 expression in the spleen. Similar responses were documented in Hmox1fl/fl controls. Nevertheless, Hmox1LysM-Cre mice show increased sensitivity to sub-lethal phenylhydrazine doses compared to Hmox1fl/fl controls. Furthermore, they upregulate HO-1 in renal proximal tubule cells following chronic administration of phenylhydrazine, indicating a failure to adapt to this challenge. In conclusion, myeloid-specific HO-1 deficiency triggers remodeling of erythrophagocytic macrophages. The plasticity of these cells depends on HO-1 expression, as a small population of monocytes that is resistant to LysM-Cre-mediated excision of HO-1 readily expands in response to hemolytic stress and populates the liver, to preserve iron homeostasis. Our data also highlight the role of Kupffer cells as the primary site of erythrophagocytosis in vivo, and demonstrate the importance of splenic macrophages and bone marrow-recruited liver macrophages as a critical alternative reserve.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Affiche Scientifique no 189, p. 302 American Journal of Hematology 92(8):E430
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 27 févr. 2019 20:21
Dernière modification: 27 févr. 2019 20:21
URI: http://espace.inrs.ca/id/eprint/6249

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