Proresolving Lipid Mediators and Mechanisms in the Resolution of Acute Inflammation

Buckley, Christopher D.; Gilroy, Derek W.; Serhan, Charles N.

doi:10.1016/j.immuni.2014.02.009

Cited by 706 publications

(740 citation statements)

References 124 publications

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“…Resolution is an active process involving the production of molecules that signal through specific cell-surface receptors to temper inflammation, enhance efferocytosis, and repair tissue damage without compromising host defense (1,(6)(7)(8). Specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids, represent a key family of resolution effectors.…”

Section: -Lipoxygenasementioning

confidence: 99%

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Cai

Thorp

Doran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

184

201

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The acute inflammatory response requires a coordinated resolution program to prevent excessive inflammation, repair collateral damage, and restore tissue homeostasis, and failure of this response contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated in part by long-chain fatty acid-derived lipid mediators called specialized proresolving mediators (SPMs). However, how SPMs are regulated during the inflammatory response, and how this process goes awry in inflammatory diseases, are poorly understood. We now show that signaling through the Mer proto-oncogene tyrosine kinase (MerTK) receptor in cultured macrophages and in sterile inflammation in vivo promotes SPM biosynthesis by a mechanism involving an increase in the cytoplasmic:nuclear ratio of a key SPM biosynthetic enzyme, 5-lipoxygenase. This action of MerTK is linked to the resolution of sterile peritonitis and, after ischemia-reperfusion (I/R) injury, to increased circulating SPMs and decreased remote organ inflammation. MerTK is susceptible to ADAM metallopeptidase domain 17 (ADAM17)-mediated cellsurface cleavage under inflammatory conditions, but the functional significance is not known. We show here that SPM biosynthesis is increased and inflammation resolution is improved in a new mouse model in which endogenous MerTK was replaced with a genetically engineered variant that is cleavage-resistant (Mertk CR ). Mertk CR mice also have increased circulating levels of SPMs and less lung injury after I/R. Thus, MerTK cleavage during inflammation limits SPM biosynthesis and the resolution response. These findings contribute to our understanding of how SPM synthesis is regulated during the inflammatory response and suggest new therapeutic avenues to boost resolution in settings where defective resolution promotes disease progression.MerTK | efferocytosis | inflammation resolution | macrophages | 5-lipoxygenase

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Section: -Lipoxygenasementioning

confidence: 99%

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Cai

Thorp

Doran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

184

201

View full text Add to dashboard Cite

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“…Unravelling the mediators that provide tissue protection and developing peptide-based drugs targeted at the resolution phase of inflammation is an exciting concept [38,39]. Amongst a host of such mediators are the melanocortins.…”

Section: Page 6 Of 39mentioning

confidence: 99%

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Kaneva

Kerrigan

Grieco

et al. 2014

Biochemical Pharmacology

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Conclusion:Melanocortin peptide pre-treatment prevented chondrocyte death following mechanical impact to cartilage and led to a marked reduction of pro-inflammatory cytokines, whilst prompting the production of anti-inflammatory/pro-resolving cytokine IL-10.Development of small molecule agonists towards melanocortin receptors could thus be a viable approach for preventing chondrocyte inflammation and death within cartilage and represent an alternative approach for the treatment of osteoarthritis.

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“…Unlike other arachidonic acid metabolites that are pro-inflammatory, such as prostaglandins and leukotrienes, lipoxins play a role in the resolution of inflammation. During the resolution phase of acute inflammation, the production of prostaglandins and leukotrienes ceases and the production of lipoxins begins; this is known as the 'lipid mediator conversion' (4,5). Lipoxins then promote macrophage clearance of the apoptotic polymorphonuclear leukocytes.…”

Section: Introductionmentioning

confidence: 99%

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

Jiang

Jiang³

et al. 2016

International Journal of Molecular Medicine

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Abstract.Although rare, acute liver failure (ALF) is associated with high levels of mortality, warranting the development of novel therapies. Nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) play roles in ALF. Lipoxin A4 (LXA4) has been shown to alleviate inflammation in non-hepatic tissues. In the present study, we explored whether LXA4 exerted hepatoprotective effects in a rat model of ALF. A rat model of ALF was generated by intraperitoneal injections of D-galactosamine (300 mg/kg) and lipopolysaccharide (50 µg/kg). Animals were randomly assigned to: control group (no ALF); model group (ALF); and the groups treated with a low dose (0.5 µg/kg), medium dose (1 µg/kg), and high dose (2 µg/kg) of LXA4 (all with ALF); and pyrrolidine dithiocarbamate (PDTC)-treated group (ALF and 100 mg/kg PDTC, an inhibitor of NF-κB). Liver histology was measured using H&E staining, serum levels by ELISA, and liver mRNA expression was measured by RT-PCR for the detection of the pro-inflammatory cytokines TNF-α and IL-6. Liver cell apoptosis (as measured using the TUNEL method and examining caspase-3 activity), and Kupffer cell NF-κB activity [using an electrophoretic mobility shift assay (EMSA)] were examined. Serum levels of transaminases, TNF-α and interleukin-6 (IL-6) were substantially higher in the model group compared to controls. In the model group, significant increases in TNF-α and IL-6 mRNA expression, TUNEL-positive cells, and caspase-3 activity in the liver tissue were noted. LXA4 improved liver pathology and significantly decreased the indicators of inflammatory response and apoptosis in a dose-dependent manner. High-dose LXA4 provided better protection than PDTC. LXA4 administration significantly decreased NF-κB expression in hepatocytes and Kupffer cells. These results indicated that LXA4 inhibited NF-κB activation, reduced the secretion of pro-inflammatory cytokines, and inhibited apoptosis of liver cells, thereby exerting protective effects against ALF.

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Proresolving Lipid Mediators and Mechanisms in the Resolution of Acute Inflammation

Cited by 706 publications

References 124 publications

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Lipoxin A4 exerts protective effects against experimental acute liver failure by inhibiting the NF-κB pathway

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