Publication
Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation
| dc.contributor.author | Wegiel, Barbara | |
| dc.contributor.author | Larsen, Rasmus | |
| dc.contributor.author | Gallo, David | |
| dc.contributor.author | Chin, Beek Yoke | |
| dc.contributor.author | Harris, Clair | |
| dc.contributor.author | Mannam, Praveen | |
| dc.contributor.author | Kaczmarek, Elzbieta | |
| dc.contributor.author | Lee, Patty J | |
| dc.contributor.author | Zuckerbraun, Brian S | |
| dc.contributor.author | Flavell, Richard | |
| dc.contributor.author | Soares, Miguel P | |
| dc.contributor.author | Otterbein, Leo E | |
| dc.date.accessioned | 2015-10-07T11:52:02Z | |
| dc.date.available | 2015-10-07T11:52:02Z | |
| dc.date.issued | 2014-11 | |
| dc.description.abstract | Microbial 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.sponsorship | NIH 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.identifier | 10.1172/JCI72853 | |
| dc.identifier.citation | J Clin Invest. 2014;124(11):4926-4940. doi:10.1172/JCI72853. | pt_PT |
| dc.identifier.doi | 10.1172/JCI72853 | |
| dc.identifier.uri | http://hdl.handle.net/10400.7/380 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.publisher | American Society for Clinical Investigation | pt_PT |
| dc.relation | Tissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases | |
| dc.relation.publisherversion | http://www.jci.org/articles/view/72853 | pt_PT |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt_PT |
| dc.title | Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation | pt_PT |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | Tissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases | |
| oaire.awardURI | info:eu-repo/grantAgreement/EC/FP7/294709/EU | |
| oaire.citation.endPage | 4940 | pt_PT |
| oaire.citation.issue | 11 | pt_PT |
| oaire.citation.startPage | 4926 | pt_PT |
| oaire.citation.title | The Journal of Clinical Investigation | pt_PT |
| oaire.citation.volume | 124 | pt_PT |
| oaire.fundingStream | FP7 | |
| project.funder.identifier | http://doi.org/10.13039/501100008530 | |
| project.funder.name | European Commission | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | article | pt_PT |
| relation.isProjectOfPublication | 370f9aad-c4ef-4e35-b754-edc840dc6b5e | |
| relation.isProjectOfPublication.latestForDiscovery | 370f9aad-c4ef-4e35-b754-edc840dc6b5e |