1. Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions
- Author
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Giulio Superti-Furga, Anna-Dorothea Gorki, Philipp Starkl, Stefan Kubicek, Keiryn L. Bennett, Michael C. Aichinger, Kilian Huber, Branka Radic-Sarikas, Rui Martins, Kari Vaahtomeri, Dontscho Kerjaschki, Ana Korosec, Omar Sharif, Thomas Decker, Stephanie C. Eisenbarth, Michael Sixt, Markus Brown, Harald Esterbauer, Sylvia Knapp, Riem Gawish, Jacques Colinge, Michelle Duggan, Karin Lakovits, Federica Quattrone, Charles-Hugues Lardeau, Simona Saluzzo, Anastasiya Hladik, Julia Maier, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
- Subjects
0301 basic medicine ,Phagocyte ,MESH: Mice, Knockout ,chemistry.chemical_compound ,Mice ,MESH: Gram-Negative Bacterial Infections ,Immunology and Allergy ,Guanine Nucleotide Exchange Factors ,MESH: RAW 264.7 Cells ,MESH: Guanine Nucleotide Exchange Factors ,MESH: Animals ,MESH: Immune Evasion ,Cytoskeleton ,cdc42 GTP-Binding Protein ,MESH: Phagocytosis ,Heme ,MESH: Sepsis ,Mice, Knockout ,Quinine ,MESH: Heme Oxygenase-1 ,MESH: Hemolysis ,Hemolysis ,3. Good health ,Anti-Bacterial Agents ,medicine.anatomical_structure ,MESH: Heme ,Female ,Guanine nucleotide exchange factor ,MESH: Membrane Proteins ,Dock8 ,MESH: Quinine ,Phagocytosis ,Immunology ,Microbiology ,Sepsis ,03 medical and health sciences ,MESH: Mice, Inbred C57BL ,MESH: Anti-Bacterial Agents ,medicine ,MESH: Cytoskeleton ,Animals ,Humans ,MESH: Mice ,Immune Evasion ,MESH: cdc42 GTP-Binding Protein ,MESH: Humans ,Macrophages ,Membrane Proteins ,MESH: Macrophages ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,RAW 264.7 Cells ,chemistry ,Gram-Negative Bacterial Infections ,MESH: Female ,Heme Oxygenase-1 ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.
- Published
- 2016
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