Age-related accumulation of mutations in the gene encoding the methylcytosine dioxygenase TET2 in hematopoietic cells is associated with a greater incidence of vascular pathology in humans. In Science, Walsh and colleagues show that reconstitution of atherosclerosis-prone Ldlr−/− mice with Tet2−/− hematopoietic stem cells (HSCs) increases the size of atherosclerotic plaques. Tet2−/− HSCs clonally expand in the immune-cell pool of recipient mice with no effect on blood cell counts, body weight, systemic insulin, glucose or cholesterol, or the proliferation or apoptosis of macrophages in the plaque. Myeloid-cell-restricted deletion of Tet2 has similar effects. In vitro, Tet2−/− macrophages exposed to low doses of oxidized low-density lipoprotein and the cytokines TNF and IFN-γ to mimic the conditions in atherosclerotic plaques have higher expression of IL-1β due to increased expression of pro-IL-1β and increased activity of the NLRP3 inflammasome. In vivo, Tet2−/− monocytes undergo more recruitment to the aortic wall than do wild-type cells. The NLRP3 inhibitor MCC950 diminishes plaque size to that in Ldlr−/− mice. These observations link age-related somatic mutations in HSCs with atherosclerosis.

Science 355, 842–847 (2017)