Clonal hematopoiesis-related mutant ASXL1 promotes atherosclerosis in mice via dysregulated innate immunity

Area of Science:

• Hematology
• Cardiovascular Biology
• Immunology

Background:

• Clonal hematopoiesis (CH) arises from somatic mutations in hematopoietic stem cells.
• ASXL1 mutations are common in CH and linked to increased cardiovascular disease (CVD) risk.
• Mechanisms connecting ASXL1 mutations to CVD remain largely unknown.

Purpose of the Study:

• To investigate the role of ASXL1 mutations in atherosclerosis development.
• To elucidate the cellular and molecular mechanisms linking ASXL1 mutations to CVDs.

Main Methods:

• Utilized Ldlr-/- mouse models with ASXL1-mutant hematopoietic cells.
• Performed transcriptome analysis on atherosclerotic plaque cells.
• Investigated the non-epigenetic role of wild-type ASXL1 in innate immune signaling pathways.

Main Results:

• ASXL1-mutant cells accelerated atherosclerosis progression in mice.
• ASXL1-mutant monocytes and macrophages displayed inflammatory gene expression signatures.
• Loss of ASXL1 function impaired inhibition of IRAK1-TAK1 interaction, leading to NF-κB activation.
• Inhibition of IRAK1/4 kinase reduced ASXL1-mutant-driven atherosclerosis and inflammatory monocytes.

Conclusions:

• Hematopoietic ASXL1 mutations promote atherosclerosis through dysregulated innate immune signaling.
• Wild-type ASXL1 acts as a cytoplasmic suppressor of innate immunity by inhibiting IRAK1-TAK1 interaction.
• ASXL1 mutations disrupt this function, activating NF-κB and contributing to CVD.
• Targeting IRAK1/4 presents a potential therapeutic strategy for CVDs associated with CH.