Editors' ChoiceAtherosclerosis

Boosting arginine metabolism to regress atherosclerosis?

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Science Translational Medicine  26 Feb 2020:
Vol. 12, Issue 532, eabb0793
DOI: 10.1126/scitranslmed.abb0793


The arginine metabolic pathway in macrophages is required to ensure continual efferocytosis and inflammation resolution.

To resolve tissue inflammation, phagocytic cells must be reprogrammed from an inflammatory state to a reparative state. Efferocytosis, the process by which macrophages clear apoptotic cells, is a key part of resolving inflammation and maintaining tissue homeostasis. In atherosclerosis, efferocytosis is impaired, which exacerbates plaque progression, disruption, and consequent ischemic cardiovascular (CV) events like myocardial infarction and stroke. It has previously been demonstrated that effective efferocytosis induces plaque regression and stabilization in mice. Therefore, new treatments that support continual efferocytosis could help prevent CV outcomes in patients.

Using a combination of in vitro and in vivo mouse models, Yurdagul et al. demonstrate that continual efferocytosis by macrophages depends on their ability to metabolize arginine following their first encounter with apoptotic cells. They implicate arginase 1 as a mediator of prolonged efferocytosis and show that it is required to induce plaque regression and stabilization in vivo. Further, they show that metabolism of arginine into ornithine and subsequently putrescine is essential for executing efferocytosis in reparative macrophages. Interestingly, putrescein treatment increases the activation of Dbl-Rac-1, a known pathway that promotes apoptotic cell engulfment, to sustain continual efferocytosis. Through this pathway, putrescein treatment results in plaque regression, with decreased necrotic cores and thickened fibrous caps in the blood vessels in mice.

Yurdagul et al.’s results reveal a previously unappreciated and essential metabolic pathway in macrophages that ensures effective efferocytosis and inflammation resolution. Because these metabolic adaptations govern effective macrophage efferocytosis and subsequent plaque regression, they represent promising targets for future studies with downstream clinical impact. The validation of this pathway in human atherosclerosis will be required as a next step before new strategies to manipulate plaque macrophage metabolism can be studied to regress plaques in humans.

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