Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe\u2212/\u2212 Mice

Yang Tang,Nan Wang,Alan R Tall,Wei Wang,Ross L Levine,Britany Woods,Trevor Fidler,Wenli Liu

doi:10.1007/s10557-020-06943-9

Abstract

ObjectiveIncreased myelopoiesis has been linked to risk of atherosclerotic cardiovascular disease (ACD). Excessive myelopoiesis can be driven by dyslipidemia and cholesterol accumulation in hematopoietic stem and progenitor cells (HSPC) and may involve increased signaling via Janus kinase 2 (JAK2). Constitutively activating JAK2 mutants drive biased myelopoiesis and promote development of myeloproliferative neoplasms (MPN) or clonal hematopoiesis, conditions associated with increased risk of ACD. JAK2 inhibitors have been developed as a therapy for MPNs. The potential for JAK2 inhibitors to protect against atherosclerosis has not been tested. We therefore assessed the impact of JAK2 inhibition on atherogenesis.MethodsA selective JAK2 inhibitor TG101348 (fedratinib) or vehicle was given to high-fat high-cholesterol Western diet (WD)–fed wild-type (WT) or Apoe−/− mice. Hematopoietic cell profiles, cell proliferation, and atherosclerosis in WT or Apoe−/− mice were assessed.ResultsTG101348 selectively reversed neutrophilia, monocytosis, HSPC, and granulocyte-macrophage progenitor (GMP) expansion in Apoe−/− mice with decreased cellular phosphorylated STAT5 and ERK1/2 and reduced cell cycling and BrdU incorporation in HSPCs, indicating inhibition of JAK/STAT signaling and cell proliferation. Ten-week WD feeding allowed the development of marked aortic atherosclerosis in Apoe−/− mice which was substantially reduced by TG101348.ConclusionsSelective JAK2 inhibition reduces atherogenesis by suppressing excessive myelopoiesis in hypercholesterolemic Apoe−/− mice. These findings suggest selective JAK2 inhibition as a potential therapeutic approach to decrease ACD risk in patients with increased myelopoiesis and leukocytosis.

Highlights

To assess the impact of TG101348 on hematopoiesis, we administered vehicle or TG101348 to Western diet (WD)-fed WT or Apoe−/− mice at a dose that sustained the plasma concentration above the cellular IC50 and effectively reduced myelopoiesis, hematocrit, and leukocytosis in a murine model of myeloproliferative neoplasms (MPN) induced by hematopoietic Jak2V617F expression [18]
Ly6Chi monocytes preferentially enter atherosclerotic lesions where they differentiate to macrophages that are actively involved in progression of atherosclerosis [24, 25]
Our studies demonstrate that TG101348 decreases atherosclerosis in Apoe−/− mice, likely by selective inhibition of hematopoietic Janus kinase 2 (JAK2) that results in suppression of excessive myelopoiesis driven by enhanced cell proliferation signaling in hematopoietic stem and progenitor cells (HSPC) and myeloid progenitors and reversal of HSPC expansion and leukocytosis

Summary

Introduction

Yang Tang and Wenli Liu are co-first author. Atherosclerosis is a lipoprotein-driven chronic inflammatory disease of the arterial wall [1]. Macrophages, neutrophils, and dendritic cells are critical players in innate and acquired immunity that are responsible for the initiation and progression of atherosclerosis. It is generally accepted that a major proportion of myeloid cells in atherosclerotic plaques are recruited from circulating blood cells. While leukocytosis could be a marker of other processes such as infection, there is considerable evidence that leukocytosis directly promotes the entry of monocytes and neutrophils into the arterial wall, increasing atherosclerosis and thrombosis [4]

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