Editors' ChoiceAtherosclerosis

Resolvin’ inflammation

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Science Translational Medicine  26 Oct 2016:
Vol. 8, Issue 362, pp. 362ec171
DOI: 10.1126/scitranslmed.aai9169

Once thought of as simply a disease of excess cholesterol deposition in the artery wall, atherosclerosis is now viewed as a disease in which inflammation drives the response to cholesterol and is a key determinant of atherosclerotic lesion growth. But why does this inflammation fail to resolve? The assumption has been that chronically elevated low-density lipoproteins in the circulation result in chronic stimulation of the inflammatory response. Fredman and colleagues now investigate whether the process of inflammation resolution is impaired in atherosclerosis, contributing to lesion development.

First, the authors interrogated specialized proresolving mediators, a class of lipid by-products that act as a brake on the inflammatory response, using lipidomics analysis of human atherosclerotic plaques. They found that proresolving mediators derived from the anti-inflammatory arm of the 5-lipoxygenase (5-LOX) pathway were decreased in advanced plaques, whereas proinflammatory 5-LOX intermediates were elevated. 5-LOX is a central hub controlling the balance of pro- and anti-inflammatory lipid mediators and achieves this balance according to whether it is in the nucleus or cytoplasm. 5-LOX in the nucleus cooperates with arachidonic acid to produce proinflammatory leukotrienes, whereas cytoplasmic 5-LOX coverts arachidonic acid and docosahexaenoic acid to lipoxins and resolvins that resolve inflammation. The authors report that human atherogenic macrophages had an elevated nuclear:cytoplasmic ratio of 5-LOX, confirming a previous report that 5-LOX is largely nuclear in advanced human atherosclerotic plaques. This may explain how the balance of leukotrienes and proresolving mediators in atherosclerotic plaques becomes disturbed, ultimately impairing the resolution of inflammation, thus enabling plaque progression.

In addition to identifying a key mechanism driving atherosclerotic lesion development, Fredman et al. tested whether supplementing the diet of an atherosclerosis mouse model with the proresolving lipid mediator RvD1 could stabilize or even reverse lesion development. The authors report that therapeutic delivery of RvD1 to mice with atherosclerosis led to improved stability of preexisting plaques, confirming that tipping the balance in favor of an anti-inflammatory response could restore blood vessel homeostasis.

G. Fredman et al., An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat. Commun. 7, 12859 (2016). [Full Text]

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