Gaseous mediators in resolution of inflammation

Wallace, John L.; Ianaro, Angela; Flannigan, Kyle L.

doi:10.1016/j.smim.2015.05.004

Cited by 97 publications

(68 citation statements)

References 105 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

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“…Recent discoveries 11–15 regarding anti-inflammatory, anti-infective and pro-resolving roles for SPMs point to their potential translational applications in harnessing endogenous resolution responses for novel host-directed therapeutic strategies in sterile and infectious inflammation. Additional roles in these homeostatic processes for non-lipid mediators of resolution will not be covered in detail here but have been recently reviewed (see REFS 16–18). Cellular and molecular mechanisms for catabasis have now been determined in multiple organ systems and diseases.…”

mentioning

confidence: 99%

Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

2015

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Specialized pro-resolving mediators (SPMs) are enzymatically derived from essential fatty acids and have important roles in orchestrating the resolution of tissue inflammation -that is, catabasis. Host responses to tissue infection elicit acute inflammation in an attempt to control invading pathogens. SPMs are lipid mediators that are part of a larger family of pro-resolving molecules, which includes proteins and gases, that together restrain inflammation and resolve the infection. These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defence. Here, we focus primarily on SPMs and their roles in lung infection and inflammation to illustrate the potent actions these mediators play in restoring tissue homeostasis after an infection.Acute inflammation is a vital response to infection that is initiated within seconds of pathogen detection 1 . Granulocytes are rapidly recruited to sites of infection 2 , where they become activated and augment the resident capacity of infected tissue to kill and ultimately clear the pathogen 3 . These early events in the host response to infection are essential for survival and are coordinated by several families of pro-inflammatory mediators, including lipid mediators (such as prostaglandins and leukotrienes), cytokines and chemokines. These pro-inflammatory mediators have overlapping and distinct functions and ultimately induce an increase in vascular permeability and orchestrate leukocyte recruitment. This leads to the cardinal signs of tissue inflammation -namely calor, rubor, tumor, dolor and potentially functio laesa (FIG. 1).Recently, a new array of molecules that function in the resolution of inflammation were elucidated and named specialized pro-resolving mediators (SPMs) 4,5 . Many of these SPMs are produced during the acute inflammatory response 6 , and their structure, biosynthesis and organic synthesis have been recently reviewed (see REF. 5). Typically, acute inflammatory responses to pathogens are self-limiting, and there is a growing appreciation that SPMs have pivotal anti-inflammatory and anti-infective roles in tissue catabasis 4 . For effective Correspondence to B.D.L. blevy@partners.org. Competing interests statementThe authors declare competing interests: see Web version for details. DATABASES ClinicalTrials.gov: http://www.clinicaltrials.gov ALL LINKS ARE ACTIVE IN THE ONLINE PDF HHS Public AccessAuthor manuscript Nat Rev Immunol. Author manuscript; available in PMC 2017 January 18. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript resolution of inflammation to occur in tissues, cessation of granulocyte recruitment is required in conjunction with the recruitment and differentiation of macrophages, which help clear inflammatory cells and tissue debris to restore tissue homeostasis 7 . Granulocytes in the tissue undergo apoptosis during the resolution of inflammation to prevent bystander tissue injury occurring from the release of potentially toxic cellular conten...

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“…Results of the study have shown that exposure of RAW 264.7 murine macrophage cells, a prototype cell line for studies on inflammation, leads to a decrease in the inflammatory response through the decrease in the production of NO as well as other important pro-inflammatory products such as cytokines. Nitric oxide, a gaseous substance acting as a signaling molecule, is produced in large amounts from the amino acid L-arginine by the enzyme inducible nitric oxide synthase (iNOS) [24]. Many inflammatory cells, most especially macrophages, express iNOS upon stimulation with bacterial LPS, viruses or even other cytokines [11].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Activity of Quantum Energy Living Body on Lipopolysaccharide-Induced Murine RAW 264.7 Macrophage Cell Line

Lee¹,

Vergara²

2016

Bioceram Dev Appl

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Gaseous mediators in resolution of inflammation

Cited by 97 publications

References 105 publications

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

Anti-Inflammatory Activity of Quantum Energy Living Body on Lipopolysaccharide-Induced Murine RAW 264.7 Macrophage Cell Line

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