Cytosolic Phospholipase A2 Plays a Key Role in the Pathogenesis of Multiple Sclerosis-like Disease

Kalyvas, Athena; David, Samuel

doi:10.1016/s0896-6273(04)00003-0

Cited by 168 publications

(152 citation statements)

References 93 publications

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“…Involvement of eicosanoids and related lipid mediators has been reported in EAE, collagen-induced arthritis, and other immunological disorders (6,7,9). Previously, we and others clearly demonstrated the importance of cPLA 2 ␣ in EAE pathology by genetically and pharmacologically ablated mouse studies (10)(11)(12). Furthermore, cPLA 2 ␣ expression and activities were up-regulated in the spinal cords (SCs) of EAE mice (13).…”

Section: Studies Of Experimental Autoimmune Encephalomyelitis (Eae)mentioning

confidence: 84%

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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Section: Studies Of Experimental Autoimmune Encephalomyelitis (Eae)mentioning

confidence: 84%

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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“…Recently, an inhibitor study showed that cPLA 2 a is also involved in autoimmune encephalomyelitis, 92) a model of multiple sclerosis. All these results have shown that the cPLA 2 a molecule itself or downstream mediators are involved in these pathologies.…”

Section: Physiological and Pathological Rolesmentioning

confidence: 99%

Regulatory Mechanism and Physiological Role of Cytosolic Phospholipase A2

Hirabayashi

Murayama

Shimizu

2004

Biological & Pharmaceutical Bulletin

214

184

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Cytosolic phospholipase A 2 a a (cPLA 2 a a) preferentially hydrolyzes phospholipids containing arachidonic acid and plays a key role in the biosynthesis of eicosanoids. This review discusses the essential features of cPLA 2 a a regulation and addresses new insights into the functional properties of this enzyme. Full activation of the enzyme requires Ca 2؉ binding to an N-terminal C2 domain and phosphorylation on serine residues. Ca 2؉ binding induces translocation of cPLA 2 a a from the cytosol to the perinuclear membranes. Serine phosphorylation is mediated by mitogen-activated protein kinases (MAPKs), Ca 2؉ /calmodulin-dependent protein kinase II, and MAPK-interacting kinase Mnk1. Interaction with proteins and lipids, which include vimentin, annexins, NADPH oxidase, phosphatidylcholine, phosphatidylinositol 4,5-bisphosphate (PIP 2 ), and ceramide-1-phosphate, can also modulate the activity of cPLA 2 a a. Recent evidence has established the physiological and pathological roles of cPLA 2 a a using cPLA 2 a a knockout mice. This enzyme has been implicated in fertility, striated muscle growth, renal concentration, postischemic brain injury, arthritis, inflammatory bone resorption, intestinal polyposis, pulmonary fibrosis, acute respiratory distress syndrome, and autoimmune encephalomyelitis. Now novel three paralogs, cPLA 2 b b, cPLA 2 g g, and cPLA 2 d d, have been identified in humans. cPLA 2 g g is distinct from others in that it is farnesylated and lacks the C2 domain. Biological roles for these new enzymes have not yet been defined.

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“…Once liberated by PLA 2 s, AA can be metabolized by a number of enzymes to create the eicosanoids. These products and AA have important functions in regulating cellular homeostasis and inflammation and have been implicated in a number of neurologic injuries (1,2).…”

mentioning

confidence: 99%

“…Transient global cerebral ischemia was shown to persistently activate cPLA 2 ␣ (9), and cPLA 2 ␣ Ϫ/Ϫ mice were significantly protected from transient focal cerebral ischemia (1). A broader role for cPLA 2 ␣ in neurologic injury was demonstrated in cPLA 2 ␣ Ϫ/Ϫ mice that suffered significantly less destruction of dopaminergic neurons following exposure to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in an experimental model of Parkinsonism (10). In rat organotypic hippocampal cultures, the cPLA 2 ␣ inhibitor arachidonyltrifluoromethyl ketone (AACOCF 3 ) protected pyramidal neurons of the CA1 region from oxygen and glucose deprivation (11).…”

mentioning

confidence: 99%

“…In rat organotypic hippocampal cultures, the cPLA 2 ␣ inhibitor arachidonyltrifluoromethyl ketone (AACOCF 3 ) protected pyramidal neurons of the CA1 region from oxygen and glucose deprivation (11). In addition, mice treated with AACOCF 3 suffered less neuronal death and had dramatically reduced induction of key cytokines and chemokines in autoimmune encephalomyelitis (2).…”

mentioning

confidence: 99%

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Cytosolic phospholipase A ₂ alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment

Shen

Kishimoto

Linden³

et al. 2007

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

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The arachidonic acid-generating enzyme cytosolic phospholipase A 2 alpha (cPLA2␣) has been implicated in the progression of excitotoxic neuronal injury. However, the mechanisms of cPLA 2␣ toxicity have yet to be determined. Here, we used a model system exposing mouse hippocampal slices to NMDA as an excitotoxic injury, in combination with simultaneous patch-clamp recording and confocal Ca 2؉ imaging of CA1 pyramidal neurons. NMDA treatment caused significantly greater injury in wild-type (WT) than in cPLA 2␣ null CA1 neurons. Bath application of NMDA evoked a slow inward current in voltage-clamped neurons (composed of both NMDA receptor-mediated and other conductances) that was smaller in cPLA 2␣ null than in WT slices. This was not due to down-regulation of NMDA receptor function because NMDA receptor-mediated currents were equivalent in each genotype following brief photolysis of caged glutamate. Current-clamp recordings were made during and following NMDA exposure by eliciting a single action potential with a brief current injection. After NMDA exposure, WT CA1 neurons developed a spike-evoked plateau potential and an increased spike-evoked dendritic Ca 2؉ transient. These effects were absent in CA1 neurons from cPLA 2␣ null mice and WT neurons treated with a cPLA 2␣ inhibitor. The Ca-sensitive K-channel toxins, apamin and paxilline, caused spike broadening and Ca 2؉ enhancement in WT and cPLA2␣ null slices. NMDA application in WT and arachidonate applied to cPLA 2␣ null cells occluded the effects of apamin/paxilline. These results indicate that cPLA 2␣ activity is required for development of aberrant electrophysiologic events triggered by NMDA receptor activation, in part through attenuation of K-channel function.action potential ͉ arachidonic acid ͉ calcium ͉ excitotoxicity ͉ inhibition T he phospholipase A 2 (PLA 2 ) enzymes catalyze ester hydrolysis of fatty acids from the second position of membrane glycerophospholipids. In mammalian cells, because this sn-2 position is highly enriched with arachidonic acid (AA), the PLA 2 s are considered the major regulated source of cellular AA. Once liberated by PLA 2 s, AA can be metabolized by a number of enzymes to create the eicosanoids. These products and AA have important functions in regulating cellular homeostasis and inflammation and have been implicated in a number of neurologic injuries (1, 2).Of the PLA 2 s expressed in the brain, the enzyme cytosolic phospholipase A 2 alpha (cPLA 2 ␣) has a unique set of biochemical properties that implicate it in AA signaling in response to neuronal activity. In response to micromolar increases in intracellular Ca 2ϩ , cPLA 2 ␣ translocates from the cytosol to cellular membranes, where its phospholipid substrate resides (3). In addition, the enzymatic activity of cPLA 2 ␣ depends upon phosphorylation by p38 MAPK (4) and ERK-2 (5). cPLA 2 ␣ has a marked preference for phospholipid substrates, with AA in the second position (6). Macrophages and mast cells derived from cPLA 2 ␣-deficient mice (cPLA 2 ␣ Ϫ/Ϫ ) are unable t...

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Cytosolic Phospholipase A2 Plays a Key Role in the Pathogenesis of Multiple Sclerosis-like Disease

Cited by 168 publications

References 93 publications

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

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

Regulatory Mechanism and Physiological Role of Cytosolic Phospholipase A2

Cytosolic phospholipase A ₂ alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment

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Cytosolic Phospholipase A2 Plays a Key Role in the Pathogenesis of Multiple Sclerosis-like Disease

Cited by 168 publications

References 93 publications

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

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

Regulatory Mechanism and Physiological Role of Cytosolic Phospholipase A2

Cytosolic phospholipase A 2 alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment

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Cytosolic phospholipase A ₂ alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment