Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux

Area of Science:

• Immunology
• Cardiovascular Research
• Molecular Biology

Background:

• Atherosclerosis is a chronic inflammatory disease where macrophages are key players.
• Janus kinase 2 (JAK2) is crucial in inflammatory and metabolic signaling.
• The Jak2^V617F mutation is linked to clonal hematopoiesis and atherosclerosis.

Purpose of the Study:

• To investigate the in vivo role of macrophage-specific JAK2 (M-Jak2) in atherosclerosis.
• To understand the mechanisms by which M-Jak2 influences atherosclerotic plaque development.

Main Methods:

• Generated atherosclerosis-prone ApoE-null mice lacking M-Jak2.
• Assessed plaque burden, macrophage proliferation, recruitment, and bone marrow clonal expansion.
• Evaluated cholesterol efflux in M-Jak2-deficient macrophages and effects of JAK2 inhibition (ruxolitinib) and a Liver X receptor agonist.

Main Results:

• M-Jak2-deficient mice showed increased atherosclerotic plaque burden.
• No significant differences were observed in macrophage proliferation, recruitment, or clonal expansion.
• M-Jak2 deficiency impaired macrophage cholesterol efflux, which was reversed by a Liver X receptor agonist.

Conclusions:

• Macrophage-specific JAK2 deficiency accelerates atherosclerosis, primarily due to impaired cholesterol efflux.
• Pharmacologic JAK2 inhibition also impairs cholesterol efflux and exacerbates atherosclerosis.
• Targeting JAK2 or enhancing cholesterol efflux may offer therapeutic strategies for atherosclerosis.