Involvement of Src‐suppressed C kinase substrate in experimental autoimmune encephalomyelitis: A link between release of astrocyte proinflammatory factor and oligodendrocyte apoptosis

Li, Xiaohong; Yan, Ming; Hu, Ling; Sun, Linlin; Zhang, Fupeng; Ji, Huoyan; Jiang, Jing; Wang, Ping; Liu, Haiou; Gao, Ying; Tao, Tao; He, Xing; Cheng, Chun; Shen, Aiguo

doi:10.1002/jnr.22355

Cited by 18 publications

(12 citation statements)

References 38 publications

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“…Apoptosis in the CNS has been linked with a number of factors including cytokines and reactive radicals [46]. Our previous data [18] as well as data presented here suggest that photobiomodulation by 670 nm light therapy could be acting via both mechanisms–down-regulation of proinflammatory cytokines and NO–to protect against disease progression.…”

Section: Discussionsupporting

confidence: 56%

Photobiomodulation Induced by 670 nm Light Ameliorates MOG35-55 Induced EAE in Female C57BL/6 Mice: A Role for Remediation of Nitrosative Stress

et al. 2013

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BackgroundExperimental autoimmune encephalomyelitis (EAE) is the most commonly studied animal model of multiple sclerosis (MS), a chronic autoimmune demyelinating disorder of the central nervous system. Immunomodulatory and immunosuppressive therapies currently approved for the treatment of MS slow disease progression, but do not prevent it. A growing body of evidence suggests additional mechanisms contribute to disease progression. We previously demonstrated the amelioration of myelin oligodendrocyte glycoprotein (MOG)-induced EAE in C57BL/6 mice by 670 nm light-induced photobiomodulation, mediated in part by immune modulation. Numerous other studies demonstrate that near-infrared/far red light is therapeutically active through modulation of nitrosoxidative stress. As nitric oxide has been reported to play diverse roles in EAE/MS, and recent studies suggest that axonal loss and progression of disability in MS is mediated by nitrosoxidative stress, we investigated the effect of 670 nm light treatment on nitrosative stress in MOG-induced EAE.MethodologyCell culture experiments demonstrated that 670 nm light-mediated photobiomodulation attenuated antigen-specific nitric oxide production by heterogenous lymphocyte populations isolated from MOG immunized mice. Experiments in the EAE model demonstrated down-regulation of inducible nitric oxide synthase (iNOS) gene expression in the spinal cords of mice with EAE over the course of disease, compared to sham treated animals. Animals receiving 670 nm light treatment also exhibited up-regulation of the Bcl-2 anti-apoptosis gene, an increased Bcl-2:Bax ratio, and reduced apoptosis within the spinal cord of animals over the course of disease. 670 nm light therapy failed to ameliorate MOG-induced EAE in mice deficient in iNOS, confirming a role for remediation of nitrosative stress in the amelioration of MOG-induced EAE by 670 nm mediated photobiomodulation.ConclusionsThese data indicate that 670 nm light therapy protects against nitrosative stress and apoptosis within the central nervous system, contributing to the clinical effect of 670 nm light therapy previously noted in the EAE model.

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Section: Discussionsupporting

confidence: 56%

Photobiomodulation Induced by 670 nm Light Ameliorates MOG35-55 Induced EAE in Female C57BL/6 Mice: A Role for Remediation of Nitrosative Stress

et al. 2013

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“…Astrocytes, a major gial cells in the CNS, and microglia play an important role in the regulation of immune responses by functioning as a source of proinflammatory cytokines, including TNF-α, IL-1β, chemokines and NO [3,11,12]. Chronically activated astrocytes and microglia are also believed to contribute to the pathology of neuroimmunological diseases including MS [10,13].…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of Myelin Gene Expression in Human Oligodendrocytes by Nitric Oxide: Implications for Demyelination in Multiple Sclerosis

Jana

Pahan²

2013

J Clin Cell Immunol

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Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS) with unknown etiology. Several studies have shown that demyelination in MS is caused by proinflammatory mediators and nitric oxide (NO), which is released by perivascular infiltrates and/or activated glial cells. Both endogenous NO released by microglia and astrocytes; and NO generated from exogenous NO donors are known to induce oligodendrocytes death. However, the molecular mechanism of oligodendroglial death is poorly understood. Here we explore the role of NO in modulating the expression of myelin-specific genes that leads to oligodendroglial death. We investigated the effect of NO on the expression of myelin basic protein (MBP), 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNPase), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) in human primary oligodendrocytes. Combination of IFN-γ and bacterial lipopolysaccharide (LPS) or double stranded RNA in the form of polyIC induced the production of NO and decreased the expression of myelin gene in human fetal mixed glial cultures. Either a scavenger of NO (PTIO) or an inhibitor of inducible nitric oxide synthase (L-NIL) abrogated (LPS+IFN-γ)- and polyIC-mediated suppression of myelin genes in human mixed glial cells. The role of NO was further corroborated by the inhibition of myelin gene expression in purified human oligodendroglia by several NO donors including SNP, NOC-7, SIN-1, and SNAP. This study illustrates a novel biological role of NO in down-regulating the expression of myelin genes preceding the death of oligodendrocytes.

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“…The cytokine TNF-α is also an important factor in the regulation of neuronal apoptotic cell death. TNF-α mRNA expression in blood mononuclear cells is correlated with disease activity in relapsing-remitting MS [26], while high IL-6 levels in the CNS [27] and TNF-α release in astrocytes [28] are correlated with the development of EAE in rats. Thus, future challenges include determining how individual cytokines and chemokines produced by astrocytes influence the development of inflammation and the behavior of infiltrating immune cell populations.…”

Section: Introductionmentioning

confidence: 99%

Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L

Kim

Hong

2011

J Neuroinflammation

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BackgroundAstrocytes, which play an active role in chronic inflammatory diseases like multiple sclerosis, exist close to mast cells with which they share perivascular localization. We previously demonstrated the possibility that astrocytes and mast cells interact in vitro and in vivo. This study aimed to investigate the signaling pathways and the role for astrocytes in the interaction of astrocytes and mast cells.MethodsWe co-cultured human U87 glioblastoma (U87) and human mast cell-1 (HMC-1) cell lines, and mouse cerebral cortices-derived astrocytes and mouse bone marrow-derived mast cells (BMMCs). Intracellular Ca2+ ([Ca2+]i) was measured by confocal microscopy; CD40 siRNA by Silencer Express Kit; small GTPases by GTP-pull down assay; PKCs, MAPKs, CD40, CD40L, Jak1/2, STAT1, TNF receptor 1 (TNFR1) by Western blot; NF-κB and AP-1 by EMSA; cytokines by RT-PCR. An experimental allergic encephalomyelitis (EAE) model was induced using myelin oligodendrocyte glycoprotein (MOG) peptide and pertussis toxin in mice. Co-localization of TNFR1 and astrocytes in EAE brain tissues was determined by immunohistochemistry.ResultsEach astrocyte co-culture had increases in [Ca2+]i levels, release of cytokines and chemokines; activities of Rho-family GTPases, NF-κB/AP-1/STAT1727, and Jack1/2, STAT1701. These effects were inhibited by anti-CD40 antibody or CD40 siRNA, and signaling pathways for Jak1/2 were inhibited by anti-TNFR1 antibody. EAE score, expression of TNFR1, and co-localization of TNFR1 and astrocytes were enhanced in brain of the EAE model. Anti-CD40 antibody or 8-oxo-dG pretreatment reduced these effects in EAE model.ConclusionsThese data suggest that astrocytes activated by the CD40-CD40L interaction in co-culture induce inflammatory cytokine production via small GTPases, and the secreted cytokines re-activate astrocytes via Jak/STAT1701 pathways, and then release more cytokines that contribute to exacerbating the development of EAE. These findings imply that the pro-inflammatory mediators produced by cell-to-cell cross-talk via interaction of CD40-CD40L may be as a promising therapeutic target for neurodegenerative diseases like MS.

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Involvement of Src‐suppressed C kinase substrate in experimental autoimmune encephalomyelitis: A link between release of astrocyte proinflammatory factor and oligodendrocyte apoptosis

Cited by 18 publications

References 38 publications

Photobiomodulation Induced by 670 nm Light Ameliorates MOG35-55 Induced EAE in Female C57BL/6 Mice: A Role for Remediation of Nitrosative Stress

Photobiomodulation Induced by 670 nm Light Ameliorates MOG35-55 Induced EAE in Female C57BL/6 Mice: A Role for Remediation of Nitrosative Stress

Down-regulation of Myelin Gene Expression in Human Oligodendrocytes by Nitric Oxide: Implications for Demyelination in Multiple Sclerosis

Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L

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