Identification of resolvin D2 receptor mediating resolution of infections and organ protection

Chiang, Nan; Dalli, Jesmond; Colas, Romain A.; Serhan, Charles N.

doi:10.1084/jem.20150225

Cited by 317 publications

(319 citation statements)

References 45 publications

(69 reference statements)

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“…Indeed, mice receiving resolving lipid mediators exhibited lesions with stability traits comparable to the baseline group, with additional improved smooth muscle cells numbers, collagen content, fibrous cap thickness, and increased numbers of reparative macrophages. In line with previous reports, 5,6,8 our in vitro studies confirmed that RvD2 and MaR1 have the ability to skew macrophage phenotype toward resolution-like, with increased TGF-β production and secretion. In accordance, and much like the lesion phenotype observed in this study, macrophage-borne TGF-β gives rise to lesions characterized by smooth muscle cell accumulation, collagen deposition, and lower macrophage numbers.…”

supporting

confidence: 92%

Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice

Viola¹,

Lemnitzer²,

Jansen³

et al. 2016

Circ Res

189

156

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Rationale: Atheroprogression is a consequence of nonresolved inflammation, and currently a comprehensive overview of the mechanisms preventing resolution is missing. However, in acute inflammation, resolution is known to be orchestrated by a switch from inflammatory to resolving lipid mediators. Therefore, we hypothesized that lesional lipid mediator imbalance favors atheroprogression. Objective: To understand the lipid mediator balance during atheroprogression and to establish an interventional strategy based on the delivery of resolving lipid mediators. Methods and Results: Aortic lipid mediator profiling of aortas from Apoe −/− mice fed a high-fat diet for 4 weeks, 8 weeks, or 4 months revealed an expansion of inflammatory lipid mediators, Leukotriene B4 and Prostaglandin E2, and a concomitant decrease of resolving lipid mediators, Resolvin D2 (RvD2) and Maresin 1 (MaR1), during advanced atherosclerosis. Functionally, aortic Leukotriene B4 and Prostaglandin E2 levels correlated with traits of plaque instability, whereas RvD2 and MaR1 levels correlated with the signs of plaque stability. In a therapeutic context, repetitive RvD2 and MaR1 delivery prevented atheroprogression as characterized by halted expansion of the necrotic core and accumulation of macrophages along with increased fibrous cap thickness and smooth muscle cell numbers. Mechanistically, RvD2 and MaR1 induced a shift in macrophage profile toward a reparative phenotype, which secondarily stimulated collagen synthesis in smooth muscle cells. Conclusions: We present evidence for the imbalance between inflammatory and resolving lipid mediators during atheroprogression. Delivery of RvD2 and MaR1 successfully prevented atheroprogression, suggesting that resolving lipid mediators potentially represent an innovative strategy to resolve arterial inflammation.

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supporting

confidence: 92%

Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice

Viola¹,

Lemnitzer²,

Jansen³

et al. 2016

Circ Res

189

156

View full text Add to dashboard Cite

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“…We observed that inhibition of the LXA 4 receptor (ALX/FPR2) or RvD2 receptor (GPR18) was insufficient to block protective LXB 4 activity. Likewise, neither 15-HETE nor RvD2 showed any direct neuroprotection, suggesting that LXB 4 signaling is specific and distinct from LXA 4 and the structurally related DHA series resolvin RvD2 (31). Hence, LXB 4 signaling warrants further investigation with respect to its neuroprotective role.…”

Section: Resultsmentioning

confidence: 91%

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Livne‐Bar¹,

Wei²,

Liu³

et al. 2017

Journal of Clinical Investigation

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“…289 In fact RvD2 was recently found to promote the resolution of acute inflammation and organ protection through the G-protein coupled receptor GPR18, which is expressed in human vascular endothelial cells. 290,291 Additionally, PGD 2 and 15 d-PGJ 2 have been shown to reduce the inflammatory activation of endothelial cells during the resolution phase of the inflammatory response. [292][293][294][295][296][297][298][299] Finally, recent studies suggest that another group of arachidonic acid-based lipids, the endocannabinoids, also have immunomodulatory activity.…”

Section: Immune-modulating Pathways In the Endotheliummentioning

confidence: 99%

Vascular endothelial cell Toll-like receptor pathways in sepsis

2015

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The endothelium forms a vast network that dynamically regulates vascular barrier function, coagulation pathways and vasomotor tone. Microvascular endothelial cells are uniquely situated to play key roles during infection and injury, owing to their widespread distribution throughout the body and their constant interaction with circulating blood. While not viewed as classical immune cells, endothelial cells express innate immune receptors, including the Toll-like receptors (TLRs), which activate intracellular inflammatory pathways mediated through NF-κB and the MAP kinases. TLR agonists, including LPS and bacterial lipopeptides, directly upregulate microvascular endothelial cell expression of inflammatory mediators. Intriguingly, TLR activation also modulates microvascular endothelial cell permeability and the expression of coagulation pathway intermediaries. Microvascular thrombi have been hypothesized to trap microorganisms thereby limiting the spread of infection. However, dysregulated activation of endothelial inflammatory pathways is also believed to lead to coagulopathy and increased vascular permeability, which together promote sepsis-induced organ failure. This article reviews vascular endothelial cell innate immune pathways mediated through the TLRs as they pertain to sepsis, highlighting links between TLRs and coagulation and permeability pathways, and their role in healthy and pathologic responses to infection and sepsis.

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Identification of resolvin D2 receptor mediating resolution of infections and organ protection

Abstract: Chiang et al. identify GPR18 as a novel receptor for resolvin D2, and show that activation of this receptor in human and mouse phagocytes stimulates phagocytic clearance during bacterial infections and promotes organ protection

Cited by 317 publications

References 45 publications

Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice

Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

Vascular endothelial cell Toll-like receptor pathways in sepsis

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