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 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 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 μg/kg) s.c., twice a day, reduced NF-κB activation and levels of proinflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor-β. 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 Aβ 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. 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 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 μg/kg) s.c., twice a day, reduced NF-κB activation and levels of proinflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor-β. 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 Aβ 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. Alzheimer disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. The neuropathological hallmarks of AD are diffuse and neuritic plaques, which are predominantly composed of the β-amyloid (Aβ) peptide, and neurofibrillary tangles, which are composed of filamentous aggregates of hyperphosphorylated tau protein.1Querfurth H.W. LaFerla F.M. Alzheimer’s disease.N Engl J Med. 2010; 362: 329-344Crossref PubMed Scopus (3652) Google Scholar Chronic inflammation due to recruitment of activated glial cells to amyloid plaques is another key pathological feature of AD, although its impact on disease progression and neurodegeneration remains an area of active investigation.2Akiyama H. Barger S. Barnum S. Bradt B. Bauer J. Cole G.M. et al.Inflammation and Alzheimer’s disease.Neurobiol Aging. 2000; 21: 383-421Abstract Full Text Full Text PDF PubMed Scopus (3644) Google Scholar Microglia play essential roles in the maintenance of homeostasis within the central nervous system, but the inflammatory program that is induced by these cells also has the potential to cause neuronal dysfunction and death if inflammatory responses are not properly resolved.3Graeber M.B. Changing face of microglia.Science. 2010; 330: 783-788Crossref PubMed Scopus (470) Google Scholar, 4Lucin K.M. Wyss-Coray T. 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Recent advances in knowledge of the mechanisms of inflammatory resolution have identified lipoxins as attractive therapeutic tools to treat diseases in which inflammation is involved.12Medeiros R. Rodrigues G.B. Figueiredo C.P. Rodrigues E.B. Grumman Jr., A. Menezes-de-Lima Jr., O. Passos G.F. Calixto J.B. Molecular mechanisms of topical anti-inflammatory effects of lipoxin A(4) in endotoxin-induced uveitis.Mol Pharmacol. 2008; 74: 154-161Crossref PubMed Scopus (47) Google Scholar, 13Sobrado M. Pereira M.P. Ballesteros I. Hurtado O. Fernandez-Lopez D. Pradillo J.M. Caso J.R. Vivancos J. Nombela F. Serena J. Lizasoain I. Moro M.A. Synthesis of lipoxin A4 by 5-lipoxygenase mediates PPARgamma-dependent, neuroprotective effects of rosiglitazone in experimental stroke.J Neurosci. 2009; 29: 3875-3884Crossref PubMed Scopus (109) Google Scholar, 14Haworth O. Cernadas M. Yang R. Serhan C.N. Levy B.D. 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Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution.Prostaglandins Leukot Essent Fatty Acids. 2005; 73: 141-162Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar Lipoxins potentiate inflammatory resolution by means of potent agonistic actions at the G-protein–coupled receptor, termed LXA4 receptor (ALX/FPR2).17Ye R.D. Boulay F. Wang J.M. Dahlgren C. Gerard C. Parmentier M. Serhan C.N. Murphy P.M. International Union of Basic and Clinical Pharmacology, LXXIII: nomenclature for the formyl peptide receptor (FPR) family.Pharmacol Rev. 2009; 61: 119-161Crossref PubMed Scopus (581) Google Scholar Activation of ALX by LXA4 reduces many endogenous processes, such as neutrophil and eosinophil recruitment and activation, leukocyte migration, NF-κB translocation, and chemokine and cytokine production. Likewise, evidence shows that LXA4 signaling primes macrophages for chemotaxis and enhances phagocytosis of microorganisms and apoptotic cells.18Serhan C.N. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways.Annu Rev Immunol. 2007; 25: 101-137Crossref PubMed Scopus (806) Google Scholar In the nervous system, LXA4 protects neurons against experimental stroke and Aβ42 toxicity by modulating inflammation.13Sobrado M. Pereira M.P. Ballesteros I. Hurtado O. Fernandez-Lopez D. Pradillo J.M. Caso J.R. Vivancos J. Nombela F. Serena J. Lizasoain I. Moro M.A. Synthesis of lipoxin A4 by 5-lipoxygenase mediates PPARgamma-dependent, neuroprotective effects of rosiglitazone in experimental stroke.J Neurosci. 2009; 29: 3875-3884Crossref PubMed Scopus (109) Google Scholar, 19Wu Y. Ye X.H. Guo P.P. Xu S.P. Wang J. Yuan S.Y. Yao S.L. Shang Y. 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Cole memory and amyloid plaques in PubMed Scopus Google Scholar at and to a on at in the the of the and by the of and with twice for C.I. Zattoni M. Serhan C.N. Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing.J Exp Med. 2007; 204: 245-252Crossref PubMed Scopus (147) Google Scholar of with and in to of and on the of the to at the of the for for with of the and a novel of The the of the that the novel the to to a the of the and to the to for after the and of a in the the with the the in the and to for with and by with The brain for in and in for a in and at The on after of and and to tissue and The and at in the the to to a and at with The in and and and of inducible nitric oxide synthase and and YM1 receptor and receptor or the with to The the of the Aβ levels as R. M. A. D. T. A. 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The activation and their role in innate and Immunol. 25: Full Text Full Text PDF PubMed Scopus Google Scholar Our data demonstrate that reduces the activation of but not receptor and receptor as by the in the NF-κB levels with and the activation of NF-κB in the in and these NF-κB activation in an effect that by ALX we the of neurons and these data that of ALX in by the recruitment and activation of alternative in Aβ Herein, we critical and evidence the endogenous LXA4 pathway as a potential to treat AD. of pathological at a of the of more anti-inflammatory the effects of to be on activation of ALX in and on and activation of NF-κB and production of proinflammatory and increased levels of anti-inflammatory Remarkably, these environmental changes in the the activation of microglia in an alternative and phagocytic phenotype, in in clearance of Aβ plaques and improvement of cognition. of Aβ in the brain is a neuropathological of AD and is to a that to the pathological of AD, and J. 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J. response in the of model of Alzheimer’s in the microglial alternative to Neurosci. 2008; PubMed Scopus Google Scholar activated macrophages are and their activation is by and receptor which in up-regulation of and S. M. A. of the and and of Immunol. Google Scholar activated levels of anti-inflammatory such as and are to play a role in the resolution of inflammation and the of tissue after the inflammatory S. activation of and 2010; Full Text Full Text PDF PubMed Scopus Google Scholar In lipoxins are key of inflammatory resolution and have been in the recruitment and activation of and represent a alternative to the Aβ clearance through the modulation of glial cell C.N. Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways.Annu Rev Immunol. 2007; 25: 101-137Crossref PubMed Scopus (806) Google Scholar, P. T. J. M. C. receptor and are critical for lipoxin A4 and J. 2010; PubMed Scopus Google Scholar, S. I. C. 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PubMed Scopus Google Scholar Such changes in the of mediators in response to the brain for the recruitment and activation of microglia in a with the that these cells may affect disease progression by modulating the buildup of Aβ through its we a reduced of Aβ after of LXA4 the reduction of Aβ to a in synaptotoxicity that resulted in improvement in cognition. for AD are and their is although many of these are with in Therefore, agents that are capable of increasing Aβ uptake by phagocytic cells is of potential therapeutic interest for AD. that lipoxins are a of endogenous lipid mediators with potent anti-inflammatory and may be potential for the of novel AD with LXA4 not affect processing and mechanisms of Aβ and of that not levels of and or and with and that is not capable of changes in the of and of as and levels are by with The represent means with is on and but not on microglia in the central nervous system. with the neuronal the and the but not with the microglial with LXA4 Aβ phagocytosis by alternative activated microglial cells for with in with Aβ42 or or and by for and demonstrate of Aβ on of cells with with cells with with a reduced of Aβ with also the up-regulation of YM1 in the of that Aβ phagocytosis in a by an effect by and that induced the YM1 up-regulation in a in the cells with reduced YM1 expression. 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