title: Carbon monoxide reverses the metabolic adaptation of microglia cells to an inflammatory stimulus.
abstract: Microglia fulfill important immunological functions in the brain by responding to pathological stresses and modulating their activities according to pro- or anti-inflammatory stimuli. Recent evidence indicates that changes in metabolism accompany the switch in microglia activation state, favoring glycolysis over oxidative phosphorylation when cells exhibit a pro-inflammatory phenotype. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory action and affects mitochondrial function in cells and tissues. In the present study, we analyzed the metabolic profile of BV2 and primary mouse microglia exposed to the CO-releasing molecules CORM-401 and CORM-A1 and investigated whether CO affects the metabolic adaptation of cells to the inflammatory stimulus lipopolysaccharide (LPS). Microglia respiration and glycolysis were measured using an Extracellular Flux Analyzer to provide a real-time bioenergetic assessment, and biochemical parameters were evaluated to define the metabolic status of the cells under normal or inflammatory conditions. We show that CO prevents LPS-induced depression of microglia respiration and reduction in ATP levels while altering the early expression of inflammatory markers, suggesting the metabolic changes induced by CO are associated with control of inflammation. CO alone affects microglia respiration depending on the concentration, as low levels increase oxygen consumption while higher amounts inhibit respiration. Increased oxygen consumption was attributed to an uncoupling activity observed in cells, at the molecular level (respiratory complex activities) and during challenge with LPS. Thus, application of CO is a potential countermeasure to reverse the metabolic changes that occur during microglia inflammation and in turn modulate their inflammatory profile.
authors.affiliation: Inserm U955, Equipe 12, Créteil 94000, France; University Paris-Est, Faculty of Medicine, Créteil 94000, France. Electronic address: jayne-louise.wilson@inserm.fr.
authors.forename: Jayne Louise
authors.initials: JL
authors.lastname: Wilson
authors.affiliation: Institut Cochin, Inserm U1016-CNRS UMR8104-Université Paris Descartes, Paris, France. Electronic address: frederic.bouillaud@inserm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouillaud
authors.affiliation: CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; Instituto de Tecnologia Química e Biológica (ITQB), Universidade Nova de Lisboa, Apartado 127, 2781-901 Oeiras, Portugal; Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2781-901 Oeiras, Portugal. Electronic address: anasofia.almeida@nms.unl.pt.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Almeida
authors.affiliation: CEDOC, NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal; Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2781-901 Oeiras, Portugal. Electronic address: helena.vieira@nms.unl.pt.
authors.forename: Helena L
authors.initials: HL
authors.lastname: Vieira
authors.affiliation: Laboratoire de Recherche sur la Croissance et la Regénération Tissulaires (CRRET), UPRESA CNRS 7053, Université Paris XII-Val de Marne, 94010 Créteil, France. Electronic address: mohand.ouidja@u-pec.fr.
authors.forename: Mohand Ouidir
authors.initials: MO
authors.lastname: Ouidja
authors.affiliation: AP-HP, Hôpital Henri Mondor-A, Chenevier,Chenevier, Service Hospitalier, Créteil, France. Electronic address: jean-luc.dubois-rande@inserm.fr.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Randé
authors.affiliation: Inserm U955, Equipe 12, Créteil 94000, France; University Paris-Est, Faculty of Medicine, Créteil 94000, France. Electronic address: roberta.foresti@inserm.fr.
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
authors.affiliation: Inserm U955, Equipe 12, Créteil 94000, France; University Paris-Est, Faculty of Medicine, Créteil 94000, France. Electronic address: roberto.motterlini@inserm.fr.
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002248:Carbon Monoxide / Q000378:metabolism*; D002460:Cell Line; D006019:Glycolysis; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D000069292:Pyroptosis / Q000235:genetics; D012119:Respiration
chemical_list: D008070:Lipopolysaccharides; D002248:Carbon Monoxide; D000255:Adenosine Triphosphate; D051547:Heme Oxygenase-1
keywords: Carbon monoxide; Glycolysis; Inflammation; Microglia; Mitochondria; Uncoupling