Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis

Kalbitz M, Fattahi F, Grailer JJ, Jajou L, Malan EA, Zetoune FS, Huber-Lang M, Russell MW, Ward PA (2016)

Publication Type: Journal article

Publication year: 2016

Journal

The FASEB Journal Federation of American Society of Experimental Biology (FASEB)

Book Volume: 30

Pages Range: 3997-4006

Journal Issue: 12

DOI: 10.1096/fj.201600728R

Abstract

Cardiac dysfunction develops during sepsis in humans and rodents. In themodel 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-proceduremice 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-1βand 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.

Involved external institutions

University of Michigan US United States (USA) (US) Universitätsklinikum Ulm DE Germany (DE)

How to cite

APA:

Kalbitz, M., Fattahi, F., Grailer, J.J., Jajou, L., Malan, E.A., Zetoune, F.S.,... Ward, P.A. (2016). Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis. The FASEB Journal, 30(12), 3997-4006. https://doi.org/10.1096/fj.201600728R

MLA:

Kalbitz, Miriam, et al. "Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis." The FASEB Journal 30.12 (2016): 3997-4006.

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