Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux

Idit Dotan,Yu Zhe Li,Josh Rapps,Edouard Al-Chami ,Jiaqi Yang,Amir Tirosh ,Carolyn L Cummins,Harsh R Desai ,Jacques Genest,Ziv Roth,Jiro Ikeda,Myron I Cybulsky ,Gary F Lewis,Changting Xiao,Helen Le,Marcela Gronda,Clinton S Robbins ,Gedaliah Farber,Sonia Rehal,Saraf Karim,Aaron D Schimmer,Kelvin Wagner ,Evan Pollock‐Tahiri ,Jenny Jongstra‐Bilen ,Michael F Saikali ,Mark D Minden,Tharini Sivasubramaniyam,Vikas Gupta,Minna Woo

doi:10.1038/s42003-022-03078-5

Abstract

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. Janus kinase 2 (JAK2) is a pivotal molecule in inflammatory and metabolic signaling, and Jak2V617F activating mutation has recently been implicated with enhancing clonal hematopoiesis and atherosclerosis. To determine the essential in vivo role of macrophage (M)-Jak2 in atherosclerosis, we generate atherosclerosis-prone ApoE-null mice deficient in M-Jak2. Contrary to our expectation, these mice exhibit increased plaque burden with no differences in macrophage proliferation, recruitment or bone marrow clonal expansion. Notably, M-Jak2-deficient bone marrow derived macrophages show a significant defect in cholesterol efflux. Pharmacologic JAK2 inhibition with ruxolitinib also leads to defects in cholesterol efflux and accelerates atherosclerosis. Liver X receptor agonist abolishes the efflux defect and attenuates the accelerated atherosclerosis that occurs with M-Jak2 deficiency. Macrophages of individuals with the Jak2V617F mutation show increased efflux which is normalized when treated with a JAK2 inhibitor. Together, M-Jak2-deficiency leads to accelerated atherosclerosis primarily through defects in cholesterol efflux from macrophages.

Highlights

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role
In order to assess the essential role of Jak[2] in macrophages in vivo, we generated ApoE-null myeloid Jak2-specific knockout mice using the creLoxP system under the control of the LysM promoter
ApoE-null LysMcre+-Jak2fl/fl were assessed and ApoE-null LysMcre+-Jak2WT/WT littermates served as controls

Summary

Introduction

Atherosclerosis is a chronic inflammatory condition in which macrophages play a major role. JAK2, a non-receptor kinase, is recruited to and phosphorylates the intracellular-cytosolic domain of the receptor This phosphorylation signals the recruitment and binding of specific STAT proteins, which in turn are phosphorylated, and dimerization leads to nuclear localization to regulate gene expression[7]. This complex signaling cascade is highly dependent on the cell type and the context in which JAK2 is activated, leading to a multitude of biological effects in cellular functions affecting growth, inflammation, and metabolism. The essential in vivo role of myeloid Jak[2] (M-Jak2) and the specific mechanisms through which it can regulate atherosclerosis is unknown

Methods

Results

Conclusion