Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase

Emerson, Mitchell R.; Levine, Steven M.

doi:10.1016/j.brainres.2004.06.045

Cited by 70 publications

(63 citation statements)

References 31 publications

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“…4B). Histological examination of the spinal cord at the peak of EAE (day 14) revealed that administration of the EP4 agonist inhibited both the infiltration of inflammatory cells and demyelination (Fig. 5 A-D).…”

Section: Resultsmentioning

confidence: 99%

“…Cytosolic phospholipase A 2 is a major form of phospholipase A 2 that is activated and liberates arachidonic acid in response to extracellular stimuli, and inhibition of this enzyme or deletion of its gene prevents EAE development in C57BL/6 mice (12,13). In contrast, deletion of the 5-lipoxygenase gene did not prevent, but instead aggravated, EAE progression (14). These findings, thus, implicate PGs in the pathogenesis of EAE.…”

mentioning

confidence: 89%

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Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Esaki

Li²,

Sakata³

et al. 2010

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

112

106

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Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4 −/− mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2 −/− mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2 −/− mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE 2 exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood-brain barrier through EP4.disease model | knockout mice | prostaglandin | prostaglandin receptor | multiple sclerosis M ultiple sclerosis (MS) is a chronic inflammatory disease of the CNS that primarily affects young adults (1, 2). The main pathological characteristics of MS include cell infiltration, demyelination, and axonal loss in the CNS. Although its etiology remains unclear, MS is thought to be a T cell-mediated autoimmune disease of the CNS in genetically susceptible individuals. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that can be induced in susceptible animals by immunization with myelin proteins or by injection of myelin proteinspecific CD4 + T cells (3). EAE has been studied intensively in investigations of the autoimmune response in the CNS, with recent studies having shown that T effector helper (Th) 17 or both Th17 and Th1 cells play a key role in disease pathogenesis (4-6). These Th cell subsets are also implicated in human MS (7-9).The concentrations of arachidonate metabolites such as prostaglandin (PG) E 2 and leukotriene C 4 are increased in the cerebrospinal fluid (CSF) of individuals with MS (10, 11). Arachidonic acid is liberated from phospholipids by the action of phospholipase A 2 and converted to PGs or leukotrienes by the action of cyclooxygenase (COX) and 5-lipoxygenase, respectively. Cytosolic phospholipase A 2 is a major form of phospholipase A 2 that is activated and liberates a...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 89%

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Esaki

Li²,

Sakata³

et al. 2010

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

112

106

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“…1B), which results in the reduction of the substrate availability for 5-LO. Emerson and LeVine reported that 5-LO Ϫ/Ϫ mice developed more severe EAE than control wild-type mice (15), suggesting a possibility of increased PGE 2 production in the SCs of 5-LO Ϫ/Ϫ mice. Meanwhile, the report raises another possibility that lipid mediators downstream of 5-LO may play protective roles in EAE pathology.…”

Section: Ep2/ep4 Signaling (32) In Addition Yao Et Al (30) Recentlmentioning

confidence: 94%

“…However, all mice treated with effective doses of indomethacin died of gastrointestinal bleeding (14). On the other hand, 5-LO Ϫ/Ϫ or 12/15-LO Ϫ/Ϫ mice developed more severe EAE than control wild-type mice (15), while pharmacological studies showed different results (12). Previous sketchy studies to focus on individual eicosanoids in EAE or MS patients have obvious limitations, as Ͼ20 different eicosanoids are produced by the concerted actions of cPLA 2 ␣ and downstream enzymes (Fig.…”

Section: Studies Of Experimental Autoimmune Encephalomyelitis (Eae) mentioning

confidence: 99%

“…5-LO generates not only LTs but also lipoxins and resolvins (46,47), which are anti-inflammatory/proresolving lipid mediators derived from AA and eicosapentaenoic acid, respectively, although we did not measure these lipid mediators in the current study. 12/15-LO deficiency conferred more severe EAE pathology (15), possibly because 12/15-LO also mediates lipoxin production. Resolvin E1 reduces dendritic cell migration and IL-12 production, suggesting a protective role in EAE pathology (48).…”

Section: Ep2/ep4 Signaling (32) In Addition Yao Et Al (30) Recentlmentioning

confidence: 99%

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Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Kihara

Matsushita

Kita

et al. 2009

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

123

107

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The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using an AA cascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD 2) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE 2 pathway is favored and the PGD2, PGI2, and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1 ؊/؊ mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-␥ than mPGES-1 ؉/؉ mice. Expression of PGE2 receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE 2-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.autoimmunity ͉ demyelination ͉ lipid mediator ͉ mass spectrometry ͉ Th17

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Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

Kim

Livne‐Bar

Gronert

et al. 2020

Molecular Nutrition Food Res

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Lipoxins (LXs) are autacoids, specialized proresolving lipid mediators (SPMs) acting locally in a paracrine or autocrine fashion. They belong to a complex superfamily of dietary small polyunsaturated fatty acid (PUFA)–metabolites, which direct potent cellular responses to resolve inflammation and restore tissue homeostasis. Together, these SPM activities have been intensely studied in systemic inflammation and acute injury or infection, but less is known about LX signaling and activities in the central nervous system. LXs are derived from arachidonic acid, an omega‐6 PUFA. In addition to well‐established roles in systemic inflammation resolution, they have increasingly become implicated in regulating neuroinflammatory and neurodegenerative processes. In particular, chronic inflammation plays a central role in Alzheimer's disease (AD) etiology, and dysregulated LX production and activities have been reported in a variety of AD rodent models and clinical tissue samples, yet with complex and sometimes conflicting results. In addition, reduced LX production following retinal injury has been reported recently by the authors, and an intriguing direct neuronal activity promoting survival and homeostasis in retinal and cortical neurons is demonstrated. Here, the authors review and clarify this growing literature and suggest new research directions to further elaborate the role of lipoxins in neurodegeneration.

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Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase

Cited by 70 publications

References 31 publications

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

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Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase

Cited by 70 publications

References 31 publications

Dual roles of PGE 2 -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Dual roles of PGE 2 -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

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Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis