{"data":{"id":"10.13016/m2c939","type":"dois","attributes":{"doi":"10.13016/m2c939","prefix":"10.13016","suffix":"m2c939","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Suresh, Rahul","nameType":"Personal","givenName":"Rahul","familyName":"Suresh","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"Activation of NLRP3 inflammasomes during complement-mediated phagocytosis by macrophages"}],"publisher":"Digital Repository at the University of Maryland","container":{},"publicationYear":2015,"subjects":[{"subject":"Immunology","subjectScheme":"pqcontrolled"},{"subject":"FOS: Clinical medicine","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subjectScheme":"pquncontrolled"}],"contributors":[],"dates":[{"date":"2015","dateType":"Issued"}],"language":"en","types":{"ris":"THES","bibtex":"phdthesis","citeproc":"thesis","schemaOrg":"Thesis","resourceType":"Dissertation","resourceTypeGeneral":"Collection"},"relatedIdentifiers":[],"relatedItems":[],"sizes":[],"formats":[],"version":null,"rightsList":[],"descriptions":[{"description":"The Complement System is an important component of innate immunity,\n\nwhose activation has been associated with acute inflammation. Activation of\n\ncomplement leads to the generation of a Membrane Attack Complex (MAC)\n\ncomposed of C5b-C9 proteins. The function of the MAC has been primarily\n\nassociated with target cell death through the polymerization and insertion of C9 on\n\nthe surface of complement activating particles. Here, I provide evidence that MAC\n\nassembled on the surface of complement activating particles, can be transferred to\n\nhost macrophages during the process of phagocytosis. This “bystander activation”\n\nonto macrophages causes potassium efflux and ROS production, which induces the\n\nassembly of the NLRP3 inflammasome, which in turn results in the activation of\n\ncaspase-1 and the processing and secretion of IL-1β and IL-18 to regulate both\n\ninnate and adaptive immunity. Inflammasome activation is not induced when\n\nmacrophages phagocytize unopsonized particles or particles opsonized with serum\n\ndeficient in one of the terminal complement components. The secretion of IL-1β\n\nand IL-18 by macrophages is dependent on NLRP3, ASC, and caspase-1, as\n\nmacrophages deficient in any one of these components fail to secrete these \n\nii\n\ncytokines following complement-mediated phagocytosis. The phagocytosis of\n\ncomplement-opsonized particles increases leukocyte recruitment and promoted\n\nTh17 biasing.\n\nLeishmania major, an intracellular pathogen, follows a similar pattern,\n\nwhen infecting macrophages: Phagocytosis of the pathogen was accompanied by\n\nthe activation of complement pathway resulting in “bystander activation” and\n\nNLRP3 inflammasome assembly. When macrophages are primed with IFN and\n\nIL-1β together prior infection, the killing of parasites is enhanced demonstrating\n\nthat IL-1β can work in concert with IFNγ to activate macrophages and thus reduce\n\nthe intracellular burden of the pathogen. This study demonstrates that the\n\nphagocytosis of complement-opsonized particles can induce inflammasome\n\nactivation by a novel mechanism involving MAC-mediated “bystander activation”\n\nof host macrophages. This work provides another mechanism whereby\n\ncomplement activation can lead to acute inflammation and identifies a previously\n\nundescribed function of the MAC to activate inflammasomes on macrophages.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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","url":"http://hdl.handle.net/1903/17107","contentUrl":null,"metadataVersion":0,"schemaVersion":"http://datacite.org/schema/kernel-2.2","source":null,"isActive":true,"state":"findable","reason":null,"viewCount":0,"viewsOverTime":[],"downloadCount":0,"downloadsOverTime":[],"referenceCount":0,"citationCount":0,"citationsOverTime":[],"partCount":0,"partOfCount":0,"versionCount":0,"versionOfCount":0,"created":"2015-09-18T06:02:31.000Z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