Clonal hematopoiesis JAKs up plaque formation

Area of Science:

• Hematology
• Cardiovascular Science
• Genetics

Background:

• Clonal hematopoiesis (CH) is the acquisition of mutations in hematopoietic stem cells (HSCs), increasing with age.
• CH is associated with age-related diseases, particularly cardiovascular disease (CVD) and atherosclerosis.
• JAK2 mutations in HSCs can cause CH and are linked to atherosclerosis, but modeling low-frequency mutations is challenging.

Purpose of the Study:

• To develop a novel low-allele-burden (LAB) mouse model for studying CH-associated atherosclerosis.
• To investigate the mechanisms linking CH, inflammation, and plaque development in a relevant disease context.
• To identify potential therapeutic targets for CH-associated CVD.

Main Methods:

• Development of a LAB mouse model by transplanting a small number of Jak2VF-mutant bone marrow cells into hyperlipidemic mice.
• Assessment of atherosclerotic plaque development in the established mouse model.
• Identification of downstream molecular targets, including phagocytic receptors and inflammatory cytokines.

Main Results:

• The LAB mouse model successfully recapitulated key features of atherosclerosis development.
• The study identified MERTK and TREM2 phagocytic receptors as downstream targets of the inflammatory cytokine IL-1.
• These findings elucidate molecular pathways involved in CH-associated cardiovascular pathology.

Conclusions:

• A novel LAB mouse model provides a valuable tool for studying CH-associated atherosclerosis.
• The IL-1 pathway and its downstream targets MERTK and TREM2 are implicated in CH-related CVD.
• These discoveries offer potential therapeutic strategies for preventing or treating CH-associated cardiovascular complications.