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Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice.

ABSTRACT: Microglia play an essential role in innate immunity, homeostasis, and neurotropic support in the central nervous system. In Alzheimer disease (AD), these cells may affect disease progression by modulating the buildup of ?-amyloid (A?) or releasing proinflammatory cytokines and neurotoxic substances. Discovering agents capable of increasing A? uptake by phagocytic cells is of potential therapeutic interest for AD. Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory properties directly involved in inflammatory resolution, an active process essential for appropriate host responses, tissue protection, and the return to homeostasis. Herein, we demonstrate that aspirin-triggered LXA4 (15 ?g/kg) s.c., twice a day, reduced NF-?B activation and levels of proinflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor-?. Such changes in the cerebral milieu resulted in recruitment of microglia in an alternative phenotype, as characterized by the up-regulation of YM1 and arginase-1 and the down-regulation of inducible nitric oxide synthase expression. Microglia in an alternative phenotype-positive cells demonstrated improved phagocytic function, promoting clearance of A? deposits and ultimately leading to reduction in synaptotoxicity and improvement in cognition. Our data indicate that activating LXA4 signaling may represent a novel therapeutic approach for AD.

SUBMITTER: Medeiros R

PROVIDER: S-EPMC3644736 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice.

Medeiros Rodrigo R Kitazawa Masashi M Passos Giselle F GF Baglietto-Vargas David D Cheng David D Cribbs David H DH LaFerla Frank M FM

The American journal of pathology 20130316 5

Microglia play an essential role in innate immunity, homeostasis, and neurotropic support in the central nervous system. In Alzheimer disease (AD), these cells may affect disease progression by modulating the buildup of β-amyloid (Aβ) or releasing proinflammatory cytokines and neurotoxic substances. Discovering agents capable of increasing Aβ uptake by phagocytic cells is of potential therapeutic interest for AD. Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory pro ...[more]

PMID: 23506847

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Project description:BackgroundSpinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation. Here, we have evaluated the effects of lipoxin A4 (LXA4), a member of a unique class of endogenous lipid mediators with both anti-inflammatory and analgesic properties, on spinal neuroinflammation and chronic pain in an experimental model of SCI.MethodsSpinal hemisection at T10 was carried out in adult male CD1 mice and Wistar rats. To test if LXA4 can reduce neuroinflammation and neuropathic pain, each animal received two intrathecal injections of LXA4 (300 pmol) or vehicle at 4 and 24 h after SCI. Sensitivity to mechanical stimulation of the hind paws was evaluated using von Frey monofilaments, and neuroinflammation was tested by measuring the mRNA and/or protein expression levels of glial markers and cytokines in the spinal cord samples after SCI. Also, microglia cultures prepared from murine cortical tissue were used to assess the direct effects of LXA4 on microglial activation and release of pro-inflammatory TNF-α.ResultsLXA4 treatment caused significant reductions in the intensity of mechanical pain hypersensitivity and spinal expression levels of microglial markers and pro-inflammatory cytokines induced by SCI, when compared to rodents receiving control vehicle injections. Notably, the increased expressions of the microglial marker IBA-1 and of the pro-inflammatory cytokine TNF-α were the most affected by the LXA4 treatment. Furthermore, cortical microglial cultures expressed ALX/FPR2 receptors for LXA4 and displayed potentially anti-inflammatory responses upon challenge with LXA4.ConclusionsCollectively, our results suggest that LXA4 can effectively modulate microglial activation and TNF-α release through ALX/FPR2 receptors, ultimately reducing neuropathic pain in rodents after spinal cord hemisection. The dual anti-inflammatory and analgesic properties of LXA4, allied to its endogenous nature and safety profile, may render this lipid mediator as new therapeutic approach for treating various neuroinflammatory disorders and chronic pain with only limited side effects.

Dataset Information

Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice.

Publications

Aspirin-triggered lipoxin A4 stimulates alternative activation of microglia and reduces Alzheimer disease-like pathology in mice.

Similar Datasets

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