CXCL4:NLRP3-mediated pyroptosis product that regulates cardiac fibrosis

Area of Science:

• Cardiovascular Biology
• Immunology
• Cell Death Mechanisms

Background:

• Severe myocarditis frequently leads to cardiac fibrosis, with the underlying mechanisms requiring further elucidation.
• NOD-like receptor protein 3 (NLRP3) inflammasome activation is implicated in myocarditis development and pyroptosis, a form of programmed cell death.
• While inhibiting NLRP3-mediated pyroptosis shows promise in reducing cardiac fibrosis, the precise mechanisms remain unclear.

Purpose of the Study:

• To investigate the relationship between pyroptosis and cardiac fibrosis in viral myocarditis (VMC) induced by CVB3 infection.
• To elucidate the role of NLRP3 inflammasome and the chemokine CXCL4 in VMC pathogenesis.
• To identify potential therapeutic targets for VMC-associated cardiac fibrosis.

Main Methods:

• Induction of VMC in mice via CVB3 infection.
• Administration of an NLRP3 inhibitor (MCC950) or use of NLRP3 knockout mice.
• Analysis of pyroptosis, CXCL4 secretion, Wnt/β-Catenin signaling, and PI3K/AKT pathway activation.
• Transcriptome sequencing to identify molecular pathways involved in CXCL4-mediated fibrosis.

Main Results:

• NLRP3 inflammasome-mediated pyroptosis in the heart was significantly inhibited by MCC950 treatment or in NLRP3 knockout mice during VMC.
• Pyroptosis of mouse myocardial fibroblasts (MCF) in VMC promoted CXCL4 secretion via activation of the Wnt/β-Catenin signaling pathway.
• Transcriptome analysis revealed that CXCL4 promotes cardiac fibrosis by activating the PI3K/AKT pathway.

Conclusions:

• CVB3 infection triggers oxidative stress, activating the NLRP3 inflammasome and leading to cardiac pyroptosis.
• MCF-derived CXCL4, induced by pyroptosis and Wnt/β-Catenin signaling, drives cardiac fibrosis through PI3K/AKT pathway activation.
• CXCL4 is identified as a key mediator in VMC-induced cardiac fibrosis, presenting a potential therapeutic target for VMC treatment.