Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis

Area of Science:

• Immunology
• Cardiology
• Molecular Biology

Background:

• Sepsis frequently causes cardiac dysfunction in humans and rodents.
• The role of the NLRP3 inflammasome in sepsis-induced cardiomyopathy is not fully understood.

Purpose of the Study:

• To investigate the role of the NLRP3 inflammasome in the heart during polymicrobial sepsis.
• To determine the mechanisms by which NLRP3 inflammasome activation occurs in cardiomyocytes.

Main Methods:

• Cecal ligation and puncture (CLP) model of polymicrobial sepsis in mice.
• Analysis of NLRP3 and IL-1β expression in cardiomyocytes (CMs) and heart tissue.
• In vitro studies using CMs exposed to lipopolysaccharide (LPS), ATP, nigericin, and recombinant C5a (rC5a).
• Assessment of reactive oxygen species (ROS) production and IL-1β release.
• Evaluation of cardiac function using echocardiography/Doppler parameters in wild-type and NLRP3 knockout mice.

Main Results:

• NLRP3 and IL-1β expression increased in mouse hearts post-CLP, particularly in CMs.
• CMs exposed to LPS plus ATP/nigericin released mature IL-1β.
• NLRP3 and IL-1β mRNA increases in CMs after CLP were dependent on C5a receptors (C5aR1/C5aR2).
• NLRP3 knockout mice exhibited reduced plasma IL-1β and IL-6 levels after CLP.
• Recombinant C5a induced C5a-receptor-dependent ROS production in CMs, which was inhibited by a NOX2 inhibitor, subsequently reducing IL-1β release.
• NLRP3 knockout mice showed preserved cardiac function after CLP.

Conclusions:

• The NLRP3 inflammasome is activated in cardiomyocytes during polymicrobial sepsis.
• Complement component C5a, acting via its receptors, contributes to NLRP3 inflammasome activation in CMs, involving ROS production.
• NLRP3 inflammasome activation exacerbates sepsis-induced cardiomyopathy.