Blockade of cytosolic phospholipase A2α prevents experimental autoimmune encephalomyelitis and diminishes development of Th1 and Th17 responses

Marušić, Suzana; Thakker, Paresh; Pelker, Jeffrey W.; Stedman, Nancy; LEE, K; McKew, John C.; Han, Lihong; Xu, Xin; Wolf, Stanley F.; BOREY, A

doi:10.1016/j.jneuroim.2008.08.012

Cited by 56 publications

(68 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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: 85%

“…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%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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

show abstract

Section: Studies Of Experimental Autoimmune Encephalomyelitis (Eae) mentioning

confidence: 85%

Section: Studies Of Experimental Autoimmune Encephalomyelitis (Eae) mentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Using one of these indole-based compounds, WAY-196025, we recently confirmed the role of cPLA 2 a in EAE (32). Prophylactic dosing limited to the duration of disease induction demonstrated that blocking cPLA 2 a during the induction phase of EAE prevented EAE development and greatly reduced Aginduced production of Th1-type cytokines and IL-17 (32). This is in agreement with recent reports suggesting that PGs, especially PGE 2 , may act directly on both human and murine T cells to facilitate their conversion to Th17 phenotype and effector cytokine production (33,34).…”

mentioning

confidence: 73%

“…These small-molecule inhibitors are highly selective for cPLA 2 a over the closely related cPLA 2 -b, -g, and -z isoforms, and block production of PGs, LTs, and PAF in whole-blood assays. Using one of these indole-based compounds, WAY-196025, we recently confirmed the role of cPLA 2 a in EAE (32). Prophylactic dosing limited to the duration of disease induction demonstrated that blocking cPLA 2 a during the induction phase of EAE prevented EAE development and greatly reduced Aginduced production of Th1-type cytokines and IL-17 (32).…”

mentioning

confidence: 82%

“…Because of this interplay of pro-and anti-inflammatory arms of the cPLA 2 pathway, the outcome of cPLA 2 a blockade during the CNS tissue-damage effector phase of EAE, which more closely represents the CNS pathological phase of MS, is not clear. Furthermore, although prophylactic dosing with cPLA 2 a inhibitors during the induction phase was efficacious in preventing EAE (32), it may not result in clinical efficacy in MS. To understand the mechanism of cPLA 2 a during the various phases of the disease and to determine the outcome of cPLA 2 a blockade during the CNS tissue-damage effector phase of EAE, we used the adoptive transfer and relapsingremitting models of EAE together with therapeutic blockade of cPLA 2 a with WAY-196025. We also compared the efficacy of cPLA 2 a blockade with that of individual blockade of downstream enzymes, COX-1 and -2 and 5-LO, to understand their relative roles in the pathogenesis of the effector phase of EAE.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cytosolic Phospholipase A2α Blockade Abrogates Disease during the Tissue-Damage Effector Phase of Experimental Autoimmune Encephalomyelitis by Its Action on APCs

Thakker

Marušić

Stedman

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

Cytosolic phospholipase A2α (cPLA2α) is the rate-limiting enzyme for release of arachidonic acid, which is converted primarily to PGs via the cyclooxygenase 1 and 2 pathways and to leukotrienes via the 5-lipoxygenase pathway. We used adoptive transfer and relapsing–remitting forms of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in two different strains of mice (SJL or C57BL/6) to demonstrate that blockade of cPLA2α with a highly specific small-molecule inhibitor during the tissue-damage effector phase abrogates the clinical manifestation of disease. Using the adoptive transfer model in SJL mice, we demonstrated that the blockade of cPLA2α during the effector phase of disease was more efficacious in ameliorating the disease pathogenesis than the blockade of each of the downstream enzymes, cyclooxygenase-1/2 and 5-lipooxygenase. Similarly, blockade of cPLA2α was highly efficacious in ameliorating disease pathogenesis during the effector phase of EAE in the adoptive transfer model of EAE in C57BL/6 mice. Investigation of the mechanism of action indicates that cPLA2α inhibitors act on APCs to diminish their ability to induce Ag-specific effector T cell proliferation and proinflammatory cytokine production. Furthermore, cPLA2α inhibitors may prevent activation of CNS-resident microglia and may increase oligodendrocyte survival. Finally, in a relapsing–remitting model of EAE in SJL mice, therapeutic administration of a cPLA2α inhibitor, starting from the peak of disease or during remission, completely protected the mice from subsequent relapses.

show abstract

Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis

Courties¹,

Baron²,

Présumey³

et al. 2011

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. Several lines of evidence implicate cytosolic phospholipase A 2 ␣ (cPLA 2 ␣) as a critical enzyme in inflammatory disorders, including rheumatoid arthritis. Since cells from the myeloid compartment regulate local and systemic disease pathogenesis, the present study was undertaken to examine the effect of cPLA 2 ␣ inhibition in experimental arthritis, using a delivery system tailored to target monocyte functions by RNA interference (RNAi).Methods. Mice with collagen-induced arthritis (CIA) were injected intravenously with an anti-cPLA 2 ␣ small interfering RNA (siRNA) sequence (siPLA2) formulated as lipoplexes with the RPR209120/DOPE cationic liposome and a carrier DNA. The clinical course of joint inflammation was assessed, and the immunologic balance was analyzed by measuring T helper cell frequencies and cytokine expression. Biodistribution studies of siRNA were also performed.Results. Weekly systemic injection of siPLA2 lipoplexes significantly reduced the incidence and severity of CIA, in both preventive and curative settings, as compared with findings in control animals. Histologic scores for inflammation and cartilage damage were reduced. The clinical effect was associated with local inhibition of tumor necrosis factor ␣ secretion and lower cPLA 2 ␣ expression and activity. The siPLA2 lipoplexes enabled triggering of in vivo RNAi-mediated gene silencing of cPLA 2 ␣ in CD11bϩ cells recovered from the spleen. While the treatment had no effect on anti-type II collagen (anti-CII) antibodies, CII-specific T helper cells producing interferon-␥, but not interleukin-17, in draining lymph node cells were decreased.Conclusion. Our findings indicate that systemic RNAi-mediated cPLA 2 ␣ gene silencing in CD11bϩ cells is effective in the treatment of CIA, and Th1 suppression is one of the potential underlying mechanisms, whereas Th17 suppression is not.Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, characterized by chronic systemic inflammation that predominantly affects articular tissue. Among the immune cells infiltrating RA joints, monocytes are abundantly represented in the synovial fluid and tissue and are considered to be major effectors of synovial inflammation. Monocytes play a key role in both the systemic and the local progression of RA, by producing molecules that participate in the inflammatory and catabolic events in the disease (1). It was recently shown that the spleen contributes to the regulation of inflammation, through monocytes that are Drs. Apparailly and Davignon contributed equally to this work. Dr. Apparailly has provided expert testimony to AERES, the French agency for research evaluation, and to an INSERM evaluation committee (CSS6); she holds patents WO 00/73481 for AAV vectors for in vivo gene therapy in rheumatoid arthritis and PCT/EP 206/ 0056765 for the use of RNA biomarkers in rheumatoid arthritis.

show abstract

Blockade of cytosolic phospholipase A2α prevents experimental autoimmune encephalomyelitis and diminishes development of Th1 and Th17 responses

Cited by 56 publications

References 53 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

Cytosolic Phospholipase A2α Blockade Abrogates Disease during the Tissue-Damage Effector Phase of Experimental Autoimmune Encephalomyelitis by Its Action on APCs

Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis

Contact Info

Product

Resources

About