Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

TLDR

Human aging increases somatic mutations in hematopoietic cells, and recurrent mutations such as in TET2 promote mutant cell expansion, a process that correlates with higher risk of atherosclerotic cardiovascular disease. The study aimed to investigate the effects of Tet2‑mutant cell expansion in atherosclerosis‑prone Ldlr‑/‑ mice. Researchers induced clonal expansion by partially reconstituting the bone marrow of Ldlr‑/‑ mice with TET2‑deficient cells. This reconstitution led to clonal expansion, markedly enlarged atherosclerotic plaques, increased NLRP3‑mediated IL‑1β secretion by macrophages, and greater atheroprotection by an NLRP3 inhibitor, supporting a causal role for somatic TET2 mutations in atherosclerosis.

Abstract

Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr-/-) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome-mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis.