BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal...

Area of Science:

• Immunology
• Cardiovascular Biology
• Epigenetics

Background:

• Clonal hematopoiesis (CH) is a risk factor for cardiovascular disease, potentially mediated by macrophage inflammasomes.
• The NLRP3 inflammasome plays a role in atherosclerosis in Tet2-deficient CH models.
• Tet2 deficiency impacts epigenetic modifications, but its link to macrophage inflammasome activation is unclear.

Purpose of the Study:

• To investigate the mechanisms of NLRP3 inflammasome activation in Tet2-deficient macrophages.
• To explore the role of epigenetic modifications in this process.
• To assess the therapeutic potential of targeting this pathway in Tet2-CH-related atherosclerosis.

Main Methods:

• Utilized cholesterol-loaded Tet2-deficient murine and human macrophages for in vitro studies.
• Employed hypercholesterolemic Ldlr-/- mice to model Tet2 CH in vivo.
• Investigated JNK1 signaling, DUSP10 expression, and BRCC3 activity.

Main Results:

• Tet2 deficiency and cholesterol synergistically increased JNK1 phosphorylation and NLRP3 inflammasome activation.
• This was linked to increased promoter methylation and reduced DUSP10 expression.
• BRCC3-mediated NLRP3 deubiquitylation was crucial; inhibition with holomycin reversed atherosclerosis and NETosis in mice and human cells.

Conclusions:

• Hypercholesterolemia and Tet2 deficiency converge on JNK1 activation and BRCC3-mediated NLRP3 activation.
• This pathway has therapeutic implications for cardiovascular disease in Tet2 CH.
• Targeting BRCC3 offers a potential treatment strategy.