Lipoxins: revelations on resolution

McMahon, Blaithin A.; Mitchell, Siobhán; Brady, Hugh R.; Godson, Catherine

doi:10.1016/s0165-6147(00)01771-5

Cited by 133 publications

(166 citation statements)

References 21 publications

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“…Lipoxin A 4 (LXA 4 ), the most studied endogenous lipoxin (12), is largely involved in immune system regulation and is linked to resolution of inflammation (13). The metabotropic ALX receptor (also called FPRL-1) is responsible for the immunological effects of LXA 4 and is expressed in peripheral organs, but has negligible occurrence in the central nervous system (CNS) (14).…”

mentioning

confidence: 99%

Anti-inflammatory lipoxin A ₄ is an endogenous allosteric enhancer of CB ₁ cannabinoid receptor

Pamplona

Ferreira

Lima

et al. 2012

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

161

198

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Allosteric modulation of G-protein–coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A 4 is an endogenous allosteric enhancer of the CB 1 cannabinoid receptor. Lipoxin A 4 was detected in brain tissues, did not compete for the orthosteric binding site of the CB 1 receptor (vs. 3 H-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A 4 displayed a CB 1 receptor-dependent protective effect against β-amyloid (1–40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB 1 receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.

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mentioning

confidence: 99%

Anti-inflammatory lipoxin A ₄ is an endogenous allosteric enhancer of CB ₁ cannabinoid receptor

Pamplona

Ferreira

Lima

et al. 2012

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

161

198

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“…8 Therefore, although their role as antiinflammatory compounds is well documented, their implication in apoptosis has been a matter of debate. 1,3,5,26 Opposite actions of LXs on the balance between survival and apoptosis have been reported in neutrophils when signaling through the pleiotropic formylpeptide receptor like-1/LXA 4 receptor. 23 This receptor binds a series of molecules, including LXA 4 , acute-phase reactant serum amyloid A (SAA) and the glucocorticoid-inducible protein annexin-1.…”

Section: Discussionmentioning

confidence: 99%

“…4 Lipoxins are mainly generated by transcellular metabolism from arachidonic acid depending on the cellular context. 5,6 In mammals, lipoxygenase enzymes (LOXs) generate two main native products: lipoxin A 4 (LXA 4 ) and B 4 (LXB 4 ), with LXA 4 being the most studied, which exerts potent anti-inflammatory actions modulating leukocyte trafficking and promoting phagocytic clearance of apoptotic cells. 7,8 The effects of LXs as lipid mediators with potent anti-inflammatory actions are well documented, but their role in apoptosis remains controversial.…”

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confidence: 99%

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

et al. 2010

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Lipoxin A 4 (LXA 4 ) is an endogenous lipid mediator that requires transcellular metabolic traffic for its synthesis. The targets of LXA 4 on neutrophils are well described, contributing to attenuation of inflammation. However, effects of lipoxins on macrophage are less known, particularly the action of LXA 4 on the regulation of apoptosis of these cells. Our data show that pretreatment of human or murine macrophages with LXA 4 at the concentrations prevailing in the course of resolution of inflammation (nanomolar range) significantly inhibits the apoptosis induced by staurosporine, etoposide and S-nitrosoglutathione or by more pathophysiological stimuli, such as LPS/IFNc challenge. The release of mitochondrial mediators of apoptosis and the activation of caspases was abrogated in the presence of LXA 4 . In addition to this, the synthesis of reactive oxygen species induced by staurosporine was attenuated and antiapoptotic proteins of the Bcl-2 family accumulated in the presence of lipoxin. Analysis of the targets of LXA 4 identified an early activation of the PI3K/Akt and ERK/Nrf-2 pathways, which was required for the observation of the antiapoptotic effects of LXA 4 . These data suggest that the LXA 4 , released after the recruitment of neutrophils to sites of inflammation, exerts a protective effect on macrophage viability that might contribute to a better resolution of inflammation.

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“…Lipoxygenase (LOX)-initiated lipid mediator pathways are important regulators of innate immunity and inflammation, since they can activate both pro-and anti-inflammatory signals (3,(17)(18)(19)(20). Recent studies have demonstrated that human pathogens such as Pseudomonas aeruginosa and Toxoplasma gondii can exploit these pathways to suppress host immune responses by expressing a functional 15-LOX and inducing LXA 4 formation (21)(22)(23).…”

mentioning

confidence: 99%

“…The human and murine 12/15-LOX pathways are of particular interest, since they are key enzymes in the formation of a distinct class of eicosanoids, the lipoxins, which are autacoids generated during inflammation and heterotypic cell-cell interactions. Lipoxin A 4 exhibits potent antiinflammatory properties in vitro and, in animal models of acute or aberrant inflammation, by inhibiting PMN (18) and lymphocyte activation (24) as well as suppressing dendritic cell function (21,22). In this regard, LXA 4 has been implicated as an important component of the endogenous counterregulatory signals that promote resolution of inflammation and limit PMNmediated tissue injury (3,18,25).…”

mentioning

confidence: 99%

A Role for the Mouse 12/15-Lipoxygenase Pathway in Promoting Epithelial Wound Healing and Host Defense

Gronert

Maheshwari

Khan

et al. 2005

Journal of Biological Chemistry

289

269

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The surface of the eye actively suppresses inflammation while maintaining a remarkable capacity for epithelial wound repair. Our understanding of mechanisms that balance inflammatory/reparative responses to provide effective host defense while preserving tissue function is limited, in particular, in the cornea. Lipoxin A 4 (LXA 4 ) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1) are lipid autacoids formed by 12/15-lipoxygenase (LOX) pathways that exhibit anti-inflammatory and neuroprotective properties. Here, we demonstrate that mouse corneas generate endogenous LXA 4 and NPD1. 12/15-LOX (Alox15) and LXA 4 receptor mRNA expression as well as LXA 4 formation were abrogated by epithelial removal and restored during wound healing. Amplification of these pathways by topical treatment with LXA 4 or NPD1 (1 g) increased the rate of re-epithelialization (65-90%, n ‫؍‬ 6 -10, p < 0.03) and attenuated the sequelae of thermal injury. In contrast, the proinflammatory eicosanoids, LTB 4 and 12R-hydroxyeicosatrienoic acid, had no impact on corneal re-epithelialization. Epithelial removal induced a temporally defined influx of neutrophils into the stroma as well as formation of the proinflammatory chemokine KC. Topical treatment with LXA 4 and NPD1 significantly increased PMNs in the cornea while abrogating KC formation by 60%. More importantly, Alox15-deficient mice exhibited a defect in both corneal re-epithelialization and neutrophil recruitment that correlated with a 43% reduction in endogenous LXA 4 formation. Collectively, these results identify a novel action for the mouse 12/15-LOX (Alox15) and its products, LXA 4 and NPD1, in wound healing that is distinct from their well established anti-inflammatory properties.

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Lipoxins: revelations on resolution

Cited by 133 publications

References 21 publications

Anti-inflammatory lipoxin A ₄ is an endogenous allosteric enhancer of CB ₁ cannabinoid receptor

Anti-inflammatory lipoxin A ₄ is an endogenous allosteric enhancer of CB ₁ cannabinoid receptor

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

A Role for the Mouse 12/15-Lipoxygenase Pathway in Promoting Epithelial Wound Healing and Host Defense

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Lipoxins: revelations on resolution

Cited by 133 publications

References 21 publications

Anti-inflammatory lipoxin A 4 is an endogenous allosteric enhancer of CB 1 cannabinoid receptor

Anti-inflammatory lipoxin A 4 is an endogenous allosteric enhancer of CB 1 cannabinoid receptor

Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

A Role for the Mouse 12/15-Lipoxygenase Pathway in Promoting Epithelial Wound Healing and Host Defense

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Anti-inflammatory lipoxin A ₄ is an endogenous allosteric enhancer of CB ₁ cannabinoid receptor

Anti-inflammatory lipoxin A ₄ is an endogenous allosteric enhancer of CB ₁ cannabinoid receptor