Complement‐induced activation of the cardiac NLRP3 inflammasome in sepsis

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. Usingthe inflamm a some protocol, exposure of cardiomyocytes (CMs) to LPS followed by ATP or nigericin caused release of mature IL-1β. Immuno staining of left ventricular frozen sections before and 8 h after CLP revealed the presence of NLRP3 and IL-1β proteins inCMs. 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, NLRP32/2 mice showed reduced plasma levels of IL-1βand IL-6. In vitro exposure of wild-type CMs to recombinant C5a (rC5a) cause delevations 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, NLRP32/2 mice had reduced defects in echo/Doppler parameters in heart afterCLP. 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. FASEB J. 30, 3997–4006 (2016). www.fasebj.org