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Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis

ABSTRACT: Background: Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease (ASCVD). Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL lowering-induced plaque remodeling or regression has not been extensively studied. Methods: To assess the effects of TET2 CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management or mice were continued on the Western diet. Results: Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area, increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, actin polymerization and endocytic vesicle trafficking. Tet2-deficient bone marrow derived macrophages (BMDMs) and Tet2+/- iPSC-derived human macrophages showed defective ability to sustain continual rounds of efferocytosis. BMDMs displayed reduced AC-binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex mediated actin polymerization; these glycolysis related defects were rescued by lactate supplementation or by treatment with the HIF-1α activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering induced plaque remodeling in Tet2+/- CH mice. Conclusions: Our data identify impaired efferocytosis and glycolysis-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce pro-resolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in TET2 CH subjects.

ORGANISM(S): Mus musculus

PROVIDER: GSE325445 | GEO | 2026/09/08

REPOSITORIES: GEO

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Project description:Regression of atherosclerosis is an important clinical goal, however the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, however numbers of these immunosuppressive cells decrease with disease progression. Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. To test if Tregs are required for the resolution of atherosclerotic inflammation and plaque regression during lipid-lowering therapy, we combined CD25 monoclonal antibody (PC61 mAb)-mediated Treg depletion with single-cell RNA-sequencing of immune cells in the plaque and conventional analyses of atherosclerosis. Single cell RNA-sequencing revealed that Tregs from aortic plaques shared some similarity with splenic Tregs, but were distinct from skin and colon Tregs supporting recent findings of tissue-dependent Treg heterogeneity. Furthermore, Tregs from progressing plaques expressed markers of natural Tregs derived from the thymus, whereas Tregs in regressing plaques lacked Nrp1 and Helios expression, suggesting that they are induced in the periphery during lipid lowering. Treatment of atherosclerotic mice with PC61 mAb effectively depleted Tregs in the blood and peripheral tissues, including plaques, and blocked the regression of atherosclerosis induced by apoB anti-sense oligonucleotides. Morphometric analyses revealed that control antibody-treated mice showed a 40% decrease in plaque burden and macrophage content under regression conditions, whereas PC61 mAb-treated mice showed no change in plaque size or inflammatory cell content compared to baseline. Moreover, Treg depletion enhanced inflammatory signaling and blocked tissue reparative functions of macrophages in the regressing plaque, including M2-polarization, efferocytosis and sensing of specialized pro-resolving lipid mediators. Together, these data establish essential roles for Tregs in the resolution of atherosclerotic inflammation and plaque remodeling during regression.

Project description:Somatic mutations that cause the clonal outgrowth of mutant hematopoietic stem cells (HSCs), known as clonal hematopoiesis (CH), decay myeloid heterogeneity, activate inflammation, and increase the risk of atherosclerosis. However, whether lifestyle alters myeloid cell diversity by either modulating CH clone expansion or the phenotypic programming of CH mutant cells, thereby impacting atherosclerosis, is unknown. Here, in humans and mice and across mutations in Jak2, Tet2, p53 and Dnmt3a, we demonstrate mutation-dependent responses to lifestyle in CH and show that mutant cells are uniquely and selectively sensitive to lifestyle exposures. Sleep and exercise restrict Jak2 and Tet2 CH and its atherogenic consequences by diminishing the clonal expansion of mutant HSCs and reprogramming mutant bone marrow (BM) HSCs and aortic macrophages, but not their neighboring wildtype (WT) counterparts, through divergent brain-body axes. In two large human datasets, moderate-to-vigorous physical associated with less non-DNMT3A CH. In atherogenic mice with Jak2 or Tet2 but not p53 or Dnmt3a CH, uninterrupted sleep or exercise curtails clone expansion. In Jak2 CH sleep and exercise do so by selectively reprogramming mutant, but not WT, BM HSCs towards anti-proliferative and metabolically healthy phenotypes by tempering BM macrophage-HSC IL-1β signaling. Sleep or exercise also lessens Jak2-, Tet2-, and p53-, but not Dnmt3a-, driven atherosclerosis, partly independent of BM clonal dynamics, by locally reprogramming mutant macrophages in atherosclerotic lesions. In Jak2 mutant, but not adjacent WT, aortic macrophages, uninterrupted sleep reduces cell death, selectively blunting CLEC4E-dependent inflammasome activation and IL-1β generation, consequently diminishing lesions. Exercise, meanwhile, activates PAC1+ neurons in the brain’s locus coeruleus (LC), raising peripheral norepinephrine (NE), and preserves the expression of NE’s adrenergic receptor (ADR) β2 in Jak2V617F, but not cohabitant WT, aortic macrophages. Exercise-mediated NE signaling from the brain’s LC to Jak2V617F aortic macrophages selectively represses their inflammatory programing and atherosclerosis. Together, our findings uncover gene-lifestyle coaction and establish that healthy lifestyles gene-specifically diminish CH and selectively reprogram mutant HSCs and macrophages to maintain myeloid heterogeneity and cardiovascular health.

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Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis

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