Endothelin-1 overexpression exacerbate experimental allergic encephalomyelitis

Guo, Vivian Yawei; Chung, Sookja K.; Siu, Chung‐Wah; Kwan, Shing-Cheong; Ho, Philip Wing-Lok; Yeung, Patrick Ka Kit; Chan, Koon‐Ho

doi:10.1016/j.jneuroim.2014.08.616

Cited by 25 publications

(23 citation statements)

References 34 publications

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“…EDN-1 receptors are upregulated on mature DCs and the disruption of autocrine endothelin signaling impairs IL-12 production and T cell stimulation by DCs 18 . In EAE, overexpression of EDN-1 exacerbates disease severity and promotes Th1 and Th17 cell expansion 71 . Lastly, recent data point to significant Nrf-2 dependent mechanisms for the repression of inflammatory cytokines 72 , thus it is conceivable that a tandem regulation of both Nrf2 and NF-κB by CDDO-DFPA and other triterpenoids may work in concert to control the induction of a TolDC phenotype.…”

Section: Discussionmentioning

confidence: 99%

A unique tolerizing dendritic cell phenotype induced by the synthetic triterpenoid CDDO-DFPA (RTA-408) is protective against EAE

Wei

Pareek

Liu

et al. 2017

Sci Rep

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Tolerogenic dendritic cells (DCs) have emerged as relevant clinical targets for the treatment of multiple sclerosis and other autoimmune disorders. However, the pathways essential for conferring the tolerizing DC phenotype and optimal methods for their induction remain an intense area of research. Triterpenoids are a class of small molecules with potent immunomodulatory activity linked to activation of Nrf2 target genes, and can also suppress the manifestations of experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that DCs are a principal target of the immune modulating activity of triterpenoids in the context of EAE. Exposure of DCs to the new class of triterpenoid CDDO-DFPA (RTA-408) results in the induction of HO-1, TGF-β, and IL-10, as well as the repression of NF-κB, EDN-1 and pro-inflammatory cytokines IL-6, IL-12, and TNFα. CDDO-DFPA exposed DCs retained expression of surface ligands and capacity for antigen uptake but were impaired to induce Th1 and Th17 cells. TGF-β was identified as the factor mediating suppression of T cell proliferation by CDDO-DFPA pretreated DCs, which failed to passively induce EAE. These findings demonstrate the potential therapeutic utility of CDDO-DFPA in the treatment and prevention of autoimmune disorders, and its capacity to induce tolerance via modulation of the DC phenotype.

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Section: Discussionmentioning

confidence: 99%

A unique tolerizing dendritic cell phenotype induced by the synthetic triterpenoid CDDO-DFPA (RTA-408) is protective against EAE

Wei

Pareek

Liu

et al. 2017

Sci Rep

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“…In treated MS patients though, such increases were not found [23]. However, in further support for a role of ET-1 in MS, ET-1 was shown to be overexpressed in a murine model of EAE [24]. …”

Section: Introductionmentioning

confidence: 99%

Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis

Desbiens

Lapointe

Gharagozloo

et al. 2016

Mediators of Inflammation

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Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized with MOG35–55 plus complete Freund's adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS.

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“…A review of the literature revealed ET-1, a potent vasoactive peptide produced by endothelial cells and reactive astrocytes [ 54 , 66 ], as a potential candidate affecting demyelinating disease. ET-1 promotes reactive astrogliosis in both MS and EAE and exacerbates clinical disease in EAE [ 54 , 67 – 70 ]. Overexpression of ET-1 by astrocytes results in severe EAE [ 67 ], while blocking ET-1 signaling ameliorates disease [ 68 ].…”

Section: Resultsmentioning

confidence: 99%

Blockade of sustained tumor necrosis factor in a transgenic model of progressive autoimmune encephalomyelitis limits oligodendrocyte apoptosis and promotes oligodendrocyte maturation

Valentin-Torres

Savarin

Barnett

et al. 2018

J Neuroinflammation

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BackgroundTumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). Although TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble TNF inhibition can promote remyelination. This has renewed interest in regulation of TNF signaling in demyelinating disease, especially given the limited treatment options for progressive MS. Using a mouse model of progressive MS, this study evaluates the effects of sustained TNF on oligodendrocyte (OLG) apoptosis and OLG precursor cell (OPC) differentiation.MethodsInduction of experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a dominant-negative interferon-γ receptor under the human glial fibrillary acidic protein promoter (GFAPγR1Δ) causes severe non-remitting disease associated with sustained TNF. Therapeutic effects in GFAPγR1Δ mice treated with anti-TNF compared to control antibody during acute EAE were evaluated by assessing demyelinating lesion size, remyelination, OLG apoptosis, and OPC differentiation.ResultsMore severe and enlarged demyelinating lesions in GFAPγR1Δ compared to wild-type (WT) mice were associated with increased OLG apoptosis and reduced differentiated CC1+Olig2+ OLG within lesions, as well as impaired upregulation of TNF receptor-2, suggesting impaired OPC differentiation. TNF blockade during acute EAE in GFAPγR1Δ both limited OLG apoptosis and enhanced OPC differentiation consistent with reduced lesion size and clinical recovery. TNF neutralization further limited increasing endothelin-1 (ET-1) expression in astrocytes and myeloid cells noted in lesions during disease progression in GFAPγR1Δ mice, supporting inhibitory effects of ET-1 on OPC maturation.ConclusionOur data implicate that IFNγ signaling to astrocytes is essential to limit a detrimental positive feedback loop of TNF and ET-1 production, which increases OLG apoptosis and impairs OPC differentiation. Interference of this cycle by TNF blockade promotes repair independent of TNFR2 and supports selective TNF targeting to mitigate progressive forms of MS.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1164-y) contains supplementary material, which is available to authorized users.

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Endothelin-1 overexpression exacerbate experimental allergic encephalomyelitis

Cited by 25 publications

References 34 publications

A unique tolerizing dendritic cell phenotype induced by the synthetic triterpenoid CDDO-DFPA (RTA-408) is protective against EAE

A unique tolerizing dendritic cell phenotype induced by the synthetic triterpenoid CDDO-DFPA (RTA-408) is protective against EAE

Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis

Blockade of sustained tumor necrosis factor in a transgenic model of progressive autoimmune encephalomyelitis limits oligodendrocyte apoptosis and promotes oligodendrocyte maturation

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