Abstract 15355: Interleukin-1beta Inhibition Attenuates Accelerated Atherosclerosis in Mice With Tet2 Loss of Function in a Sex-dependent Fashion

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) describes somatic mutations of bone marrow derived blood cells in the absence of overt hematological disease. CHIP correlates with aging and atherosclerotic cardiovascular diseases in humans. Tet2 mutations, common in CHIP, augment atherosclerosis. Tet2 -deficient macrophages over-express Interleukin-(IL)1β mRNA in response to LDL. IL-1β neutralization reduces recurrent events in patients post myocardial infarction with residual inflammatory risk.We previously showed that IL-1β neutralization reduces evolution of established mouse atherosclerosis. Hypothesis: This study tested the hypothesis that IL-1β neutralization will reduce early accelerated atherosclerosis caused by Tet2 deficiency in hematopoietic cells. Methods: We transplanted lethally irradiated LDL-R -/- atherosclerotic prone mice with either Tet2 +/+ or Tet2 - /- bone marrow cells. Chimeric mice consumed a western diet and received a selective anti-mouse IL-1β monoclonal antibody or isotype-matched control. After nine weeks of treatment, we analyzed atherosclerotic lesions morphologically and by single cell mRNA analysis. Results: IL-1β neutralization reduced accelerated atherosclerosis associated with Tet2 deficiency in female but not in male mice (Table). Single cell RNA-sequencing analysis of the dissociated aortic arch revealed differences in macrophage expression of genes involved in innate immune response interleukin signaling pathways between male and female mice. Conclusions: This unexpected sex-dependence of accelerated atherogenesis in Tet2 - /- bone-marrow mice on IL-1β signaling lays the ground for further mechanistic exploration.