title: Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis.
abstract: Cardiac dysfunction develops during sepsis in humans and rodents. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we investigated the role of the NLRP3 inflammasome in the heart. Mouse heart homogenates from sham-procedure mice contained high mRNA levels of NLRP3 and IL-1β. Using the inflammasome protocol, exposure of cardiomyocytes (CMs) to LPS followed by ATP or nigericin caused release of mature IL-1β. Immunostaining of left ventricular frozen sections before and 8 h after CLP revealed the presence of NLRP3 and IL-1β proteins in CMs. CLP caused substantial increases in mRNAs for IL-1β and NLRP3 in CMs which are reduced in the absence of either C5aR1 or C5aR2. After CLP, NLRP3-/-mice showed reduced plasma levels of IL-1β and IL-6. In vitro exposure of wild-type CMs to recombinant C5a (rC5a) caused elevations in both cytosolic and nuclear/mitochondrial reactive oxygen species (ROS), which were C5a-receptor dependent. Use of a selective NOX2 inhibitor prevented increased cytosolic and nuclear/mitochondrial ROS levels and release of IL-1β. Finally, NLRP3-/-mice had reduced defects in echo/Doppler parameters in heart after CLP. These studies establish that the NLRP3 inflammasome contributes to the cardiomyopathy of polymicrobial sepsis.-Kalbitz, M., Fattahi, F., Grailer, J. J., Jajou, L., Malan, E. A., Zetoune, F. S., Huber-Lang, M., Russell, M. W., Ward, P. A. Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Department of Orthopaedic Trauma, Hand, Plastic, and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; and.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kalbitz
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Fattahi
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Jamison J
authors.initials: JJ
authors.lastname: Grailer
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Jajou
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Malan
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Firas S
authors.initials: FS
authors.lastname: Zetoune
authors.affiliation: Department of Orthopaedic Trauma, Hand, Plastic, and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Huber-Lang
authors.affiliation: Department of Pediatric Cardiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Russell
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; pward@umich.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000818:Animals; D015936:Complement C5a / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C573346:Nlrp3 protein, rat; D017382:Reactive Oxygen Species; D015936:Complement C5a
keywords: C5a; C5a receptors; CLP; IL-1β