Macrophage Jak2 deficiency accelerates atherosclerosis through defects in cholesterol efflux
Idit Dotan, Jiaqi Yang, Jiro Ikeda, Ziv Roth, Evan Pollock‐Tahiri, Harsh R. Desai, Tharini Sivasubramaniyam, Sonia Rehal, Josh Rapps, Yu Zhe Li, Helen Le, Gedaliah Farber, Edouard Al-Chami, Changting Xiao, Saraf Karim, Marcela Gronda, Michael F. Saikali, Amit Tirosh, Kay‐Uwe Wagner, Jacques Genest, Aaron D. Schimmer, Vikas Gupta, Mark D. Minden, Carolyn L. Cummins, Gary F. Lewis, Clinton S. Robbins, Jenny Jongstra‐Bilen, Myron I. Cybulsky, Minna Woo
Abstract
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 Jak2 V617F 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 Jak2 V617F 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.