Resolving the links between efferocytosis and DNMT3A mutation–driven clonal hematopoiesis in atherosclerosis
Aarti Asnani
Aarti Asnani
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Commentary

Resolving the links between efferocytosis and DNMT3A mutation–driven clonal hematopoiesis in atherosclerosis

Abstract

Efferocytosis, or the clearance of apoptotic cells by macrophages, has been implicated in tissue resolution that promotes disease regression in atherosclerosis and other diseases of chronic inflammation. The mechanisms by which efferocytosis leads to pro-resolving macrophage reprogramming have not been fully defined. In this issue of the JCI, Avrampou and colleagues found that efferocytosis activates DNA-methyltransferase-3A (DNMT3A) to promote base excision repair and suppress oxidized DNA. Moreover, they provide evidence that DNMT3A enabled tissue repair in the context of plaque regression in a mouse model of atherosclerosis. Human studies have linked DNMT3A mutation–mediated clonal hematopoiesis (DNMT3A-CH) with atherosclerosis. The findings of Avrampou et al. linking DNMT3A function to efferocytosis-mediated tissue repair suggest that this pathway could be modulated therapeutically to minimize cardiovascular events in patients.

Authors

Aarti Asnani

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Figure 1

DNMT3A activation is linked to DNA repair, efferocytosis, and plaque resolution in a mouse model of atherosclerosis.

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DNMT3A activation is linked to DNA repair, efferocytosis, and plaque res...
Avrampou et al. (11) observed that efferocytosis stimulated proliferation of pro-resolving macrophages through a base excision repair pathway that requires DNMT3A activation. Noting that DNMT3A mutation–driven clonal hematopoiesis (DNMT3A-CH) is associated with coronary heart disease and atherosclerosis (7, 8), the authors found that LDL-lowering regimens failed to induce atherosclerotic plaque stabilization in DNMT3A-CH mice. These findings solidify the connection between DNMTA3 function, efferocytosis, and resolution within plaques. SAM, S-adenosylmethionine.