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Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation

dc.contributor.authorWegiel, Barbara
dc.contributor.authorLarsen, Rasmus
dc.contributor.authorGallo, David
dc.contributor.authorChin, Beek Yoke
dc.contributor.authorHarris, Clair
dc.contributor.authorMannam, Praveen
dc.contributor.authorKaczmarek, Elzbieta
dc.contributor.authorLee, Patty J
dc.contributor.authorZuckerbraun, Brian S
dc.contributor.authorFlavell, Richard
dc.contributor.authorSoares, Miguel P
dc.contributor.authorOtterbein, Leo E
dc.date.accessioned2015-10-07T11:52:02Z
dc.date.available2015-10-07T11:52:02Z
dc.date.issued2014-11
dc.description.abstractMicrobial clearance by eukaryotes relies on complex and coordinated processes that remain poorly understood. The gasotransmitter carbon monoxide (CO) is generated by the stress-responsive enzyme heme oxygenase-1 (HO-1, encoded by Hmox1), which is highly induced in macrophages in response to bacterial infection. HO-1 deficiency results in inadequate pathogen clearance, exaggerated tissue damage, and increased mortality. Here, we determined that macrophage-generated CO promotes ATP production and release by bacteria, which then activates the Nacht, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome, intensifying bacterial killing. Bacterial killing defects in HO-1-deficient murine macrophages were restored by administration of CO. Moreover, increased CO levels enhanced the bacterial clearance capacity of human macrophages and WT murine macrophages. CO-dependent bacterial clearance required the NALP3 inflammasome, as CO did not increase bacterial killing in macrophages isolated from NALP3-deficient or caspase-1-deficient mice. IL-1β cleavage and secretion were impaired in HO-1-deficient macrophages, and CO-dependent processing of IL-1β required the presence of bacteria-derived ATP. We found that bacteria remained viable to generate and release ATP in response to CO. The ATP then bound to macrophage nucleotide P2 receptors, resulting in activation of the NALP3/IL-1β inflammasome to amplify bacterial phagocytosis by macrophages. Taken together, our results indicate that macrophage-derived CO permits efficient and coordinated regulation of the host innate response to invading microbes.pt_PT
dc.description.sponsorshipNIH grants: (HL-071797, HL-076167, HL-106227), American Heart Association grants: (10SDG2640091 and NIH R21CA169904-01), Julie Henry Fund, Transplant Center of the BIDMC, FCT grants: (SFRH/BPD/25436/2005, PTDC/BIO/70815/2006, PTDC/BIA-BCM/101311/2008, PTDC/SAU-FCF/100762/2008), the European Community, 6th Framework grant LSH-2005-1.2.5-1 and ERC-2011-AdG, Howard Hughes Medical Institute.pt_PT
dc.identifier10.1172/JCI72853
dc.identifier.citationJ Clin Invest. 2014;124(11):4926-4940. doi:10.1172/JCI72853.pt_PT
dc.identifier.doi10.1172/JCI72853
dc.identifier.urihttp://hdl.handle.net/10400.7/380
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Society for Clinical Investigationpt_PT
dc.relationTissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases
dc.relation.publisherversionhttp://www.jci.org/articles/view/72853pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleMacrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/294709/EU
oaire.citation.endPage4940pt_PT
oaire.citation.issue11pt_PT
oaire.citation.startPage4926pt_PT
oaire.citation.titleThe Journal of Clinical Investigationpt_PT
oaire.citation.volume124pt_PT
oaire.fundingStreamFP7
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication370f9aad-c4ef-4e35-b754-edc840dc6b5e
relation.isProjectOfPublication.latestForDiscovery370f9aad-c4ef-4e35-b754-edc840dc6b5e

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