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5-Androstenediol Ameliorates Pleurisy, Septic Shock, and Experimental Autoimmune Encephalomyelitis in Mice  [PDF]
Ferdinando Nicoletti,Dominick L. Auci,Katia Mangano,Jaime Flores-Riveros,Sonia Villegas,James M. Frincke,Christopher L. Reading,Halina Offner
Autoimmune Diseases , 2010, DOI: 10.4061/2010/757432
Abstract: Androstenediol (androst-5-ene-3 ,17 -diol; 5-AED), a natural adrenal steroid, has been shown to suppress experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice. We here report that 5-AED limits inflammation and proinflammatory cytokines including TNF in murine models of carrageenan-induced pleurisy and lippopolysaccaride- (LPS) induced septic shock. 5-AED binds to and transactivates sex steroid receptors with the same general rank order of potency (ERβ > ERα ? AR). 5-AED provides benefit in EAE in a dose-dependent fashion, even when treatment is delayed until onset of disease. The minimally effective dose may be as low as 4?mg/kg in mice. However, benefit was not observed when 5-AED was given in soluble formulation, leading to a short half-life and rapid clearance. These observations suggest that treatment with 5-AED limits the production of pro-inflammatory cytokines in these animal models and, ultimately, when formulated and administered properly, may be beneficial for patients with multiple sclerosis and other Th1-driven autoimmune diseases. 1. Introduction Nonglucocorticoid steroids are subjects of intense scientific investigation as perturbations are associated with various diseases including the pathogenesis of autoimmunity [1]. The “gender gap” [2] with respect to incidence and severity of autoimmune disease has been the focus of efforts to uncover new therapies. For example, estrogens [3] and androgens [4, 5] are protective in several autoimmune disease models, including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Recent work has dissociated the anti-inflammatory effect from the neuroprotective effect of estrogen treatment in EAE and has shown that its neuroprotective effects do not necessarily depend on anti-inflammatory properties [6]. Specifically, an estrogen receptor (ER) agonist reduced central nervous system inflammation, whereas an ER agonist treatment did not, but instead, was neuroprotective. Preliminary clinical results were encouraging. In a pilot trial, oral estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging [7]. However, sex steroid therapy involves serious risks. For example, estrogen treatment involves increased risk for breast cancer in women [8]. Because such estrogen-related toxicities are mediated almost exclusively through ER , ER ligand treatment has been suggested as a potentially safer neuroprotective strategy in multiple sclerosis and other
Greatly attenuated experimental autoimmune encephalomyelitis in aquaporin-4 knockout mice
Lihua Li, Hua Zhang, AS Verkman
BMC Neuroscience , 2009, DOI: 10.1186/1471-2202-10-94
Abstract: We investigated the involvement of AQP4 in disease severity in an established mouse model of experimental autoimmune encephalomyelitis (EAE) produced by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) peptide. EAE was remarkably attenuated in AQP4 null mice compared to identically treated wildtype mice. Whereas most wildtype mice developed progressive tail and hindlimb paralysis, clinical signs were virtually absent in AQP4 null mice. Brain and spinal cords from AQP1 null mice showed greatly reduced mononuclear cell infiltration compared to wildtype mice, with relatively little myelin loss and axonal degeneration.The reduced severity of autoimmune encephalomyelitis in AQP4 deficiency suggests AQP4 as a novel determinant in autoimmune inflammatory diseases of the central nervous system and hence a potential drug target.Aquaporin-4 (AQP4) is a water-selective channel expressed in plasma membranes of astrocytes throughout the central nervous system (CNS), particularly at astrocyte foot processes at the blood-brain barrier and brain-cerebrospinal fluid interfaces [1,2]. AQP4 facilitates water movement in the brain and spinal cord, astrocyte migration, and neuroexcitatory phenomena (reviewed in ref. [3]). Mice lacking AQP4 manifest remarkable phenotype differences from wildtype mice in models of cytotoxic [4] and vasogenic [5] cerebral edema, brain injury associated with glial scarring [6], epilepsy [7] and cortical spreading depression [8]. Structural data on AQP4 from electron crystallography suggested a possible new role of AQP4 in cell-cell adhesion [9,10], though subsequent experimental studies did not confirm this role [11].Another potential new role for AQP4 that is unrelated to its cell membrane water transport function was suggested by the discovery of circulating autoantibodies against AQP4 in most patients with the inflammatory demyelinating disease neuromyelitis optica (NMO) [12]. Indirect evidence, including correlations of NMO-IgG titer wit
Interferon regulatory factor-7 modulates experimental autoimmune encephalomyelitis in mice
Mohammad Salem, Jyothi T Mony, Morten L?bner, Reza Khorooshi, Trevor Owens
Journal of Neuroinflammation , 2011, DOI: 10.1186/1742-2094-8-181
Abstract: The role of IRF7 in development of EAE was studied by immunizing IRF7-KO and C57BL/6 (WT) mice with myelin oligodendrocyte glycoprotein using a standard protocol for the induction of EAE. We measured leukocyte infiltration and localization in the CNS using flow cytometric analysis and immunohistochemical procedures. We determined levels of CD3 and selected chemokine and cytokine gene expression by quantitative real-time PCR.IRF7 gene expression increased in the CNS as disease progressed. IRF7 message was localized to microglia and infiltrating leukocytes. Furthermore, IRF7-deficient mice developed more severe disease. Flow cytometric analysis showed that the extent of leukocyte infiltration into the CNS was higher in IRF7-deficient mice with significantly higher number of infiltrating macrophages and T cells, and the distribution of infiltrates within the spinal cord was altered. Analysis of cytokine and chemokine gene expression by quantitative real-time PCR showed significantly greater increases in CCL2, CXCL10, IL-1β and IL17 gene expression in IRF7-deficient mice compared with WT mice.Together, our findings suggest that IRF7 signaling is critical for regulation of inflammatory responses in the CNS.Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which is likely triggered by infection or other environmental events [1,2]. Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS that is induced by immunization with myelin antigens [3]. In both MS and EAE demyelinating lesions are accompanied by T cell and macrophage infiltration [2,3].The first clinically approved therapy for MS was IFN-β [4,5], a member of the type I IFN family that also includes multiple IFN-α subtypes. Type I IFNs are classically induced by viral infection and act through a common receptor, IFNAR [6]. The transcription factor IRF7 is constitutively expressed at low levels in the cytoplasm [7,8], and becomes activated by
Deletion of UCP2 in iNOS Deficient Mice Reduces the Severity of the Disease during Experimental Autoimmune Encephalomyelitis  [PDF]
Caroline Aheng,Nathalie Ly,Mairead Kelly,Saleh Ibrahim,Daniel Ricquier,Marie-Clotilde Alves-Guerra,Bruno Miroux
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022841
Abstract: Uncoupling protein 2 is a member of the mitochondrial anion carrier family that is widely expressed in neurons and the immune cells of humans. Deletion of Ucp2 gene in mice pre-activates the immune system leading to higher resistance toward infection and to an increased susceptibility to develop chronic inflammatory diseases as previously exemplified with the Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for multiple sclerosis. Given that oxidative stress is enhanced in Ucp2?/? mice and that nitric oxide (NO) also plays a critical function in redox balance and in chronic inflammation, we generated mice deficient for both Ucp2 and iNos genes and submitted them to EAE. Mice lacking iNos gene exhibited the highest clinical score (3.4+/?0.5 p<0.05). Surprisingly, mice deficient for both genes developed milder disease with reduced immune cell infiltration, cytokines and ROS production as compared to iNos?/? mice.
Inhibition of Experimental Autoimmune Encephalomyelitis in Human C-Reactive Protein Transgenic Mice Is Fc RIIB Dependent  [PDF]
Xian-Zhen Hu,Tyler T. Wright,Nicholas R. Jones,Theresa N. Ramos,Gregory A. Skibinski,Mark A. McCrory,Scott R. Barnum,Alexander J. Szalai
Autoimmune Diseases , 2011, DOI: 10.4061/2011/484936
Abstract: We showed earlier that experimental autoimmune encephalomyelitis (EAE) in human C-reactive protein (CRP) transgenic mice (CRPtg) has delayed onset and reduced severity compared to wild-type mice. Since human CRP is known to engage Fc receptors and Fc receptors are known to play a role in EAE in the mouse, we sought to determine if Fc RI, Fc RIIb, or Fc RIII was needed to manifest human CRP-mediated protection of CRPtg. We report here that in CRPtg lacking either of the two activating receptors, Fc RI and Fc RIII, the beneficial effects of human CRP are still observed. In contrast, if CRPtg lack expression of the inhibitory receptor Fc RIIB, then the beneficial effect of human CRP is abrogated. Also, subcutaneous administration of purified human CRP stalled progression of ongoing EAE in wild-type mice, but similar treatment failed to impede EAE progression in mice lacking Fc RIIB. The results reveal that a axis is responsible for protection against EAE in the CRPtg model. 1. Introduction C-reactive protein (CRP) is a widely used blood marker of inflammation [1], but it is increasingly apparent that the protein plays a causal role in host defense against microbial pathogens [2] and in cardiovascular disease [3]. Furthermore, in at least three different mouse models, human CRP has been shown to protect against autoimmune disease [4–6]. Importantly, we showed that human CRP transgenic mice (CRPtg) are resistant to experimental autoimmune encephalomyelitis (EAE) [6], an animal model of multiple sclerosis (MS). Thus in CRPtg compared to wild-type mice, EAE onset was delayed, its severity was attenuated, and infiltration of encephalitogenic T-cells and monocytes/macrophages into the CNS was prevented [6]. The encephalitogenic cells with which CRP interacts to manifest protection in EAE and the mode of action of human CRP on these cells were not identified. Since human CRP binds both human and mouse Fc receptors [7–10] and because there is growing evidence that Fc receptors play a major role in controlling the emergence of EAE and other autoimmune diseases [11–15], we sought to determine if FcγRs were required for human CRP-mediated protection against EAE in the mouse. Here we show that for CRPtg mice lacking expression of the activating receptors FcγRI and FcγRIII, expression of human CRP delays onset and reduces severity of EAE as well as or better than it does in CRPtg with an intact FcγR repertoire. In contrast in CRPtg mice that lack expression of the inhibitory receptor, FcγRIIB, no human CRP-mediated protection from EAE is observed. Likewise,
Effect of Vitamin D3 on Ifn-Γ and Il-10 Levels in Mice with Experimental Autoimmune Encephalomyelitis
Gh Mosayebi,A Ghazavi,MA Payani
Journal of Shahid Sadoughi University of Medical Sciences , 2007,
Abstract: Introduction: Multiple sclerosis (MS) is a chronic autoimmune disease with unknown etiology affecting the central nervous system. The prevalence of MS is highest where environmental supplies of vitamin D are lowest. Some studies have shown a strong protective effect of vitamin D3 in experimental autoimmune encephalomyelitis (EAE); a model of MS. However, it is not known whether vitamin D3 has a protective effect in EAE. Vitamin D3 may be inhibit EAE by having an effect on TH1 and TH2 immune responses. To address this question, the effect of vitamin D3 on cellular immune responses in C57BL/6 mice with experimental autoimmune encephalomyelitis was investigated. Methods: Male C57BL/6 mice matched in age and weight were placed in two therapeutic groups (n=10 per group) as follows: Vitamin D3-treated EAE mice (5μg/kg/every two days of vitamin D3 given i.p from day -3 until day +19 after disease induction). Non-treated EAE mice (EAE control) received vehicle alone with same schedule. 20 days after immunization, the mononuclear cells (MNCs) of the spleen were isolated from mice and cultured in the presence and absence of MOG35-55 for 96 hours. The supernatant of cultured cells was collected and produced cytokines (IL-10 and IFN-γ) were assayed by ELISA. Results: The results showed that vitamin D3-treated mice had less severe clinical signs and synptoms of EAE (3.2±0.8) than non-treated EAE induced mice (5.3±0.44), (p=0.001). Also, there was a significant difference regarding the day of onset of disease in the vitamin D3-treated and non treated EAE-induced mice (day 15±1 and day 11±1, respectively). There was no significant difference in IFN-γ production between treated and non-treated mice, but the amount of IL-10 production in the D3-treated mice was higher than the non-treated group (p=0.001). Conclusion: Considering the role of TH1 in the pathogenesis of EAE and MS, it is suggested that vitamin D3 can reduce or delay the onset of EAE by shifting immune responses to TH2 and IL-10 production. Thus, vitamin D3 as an immune modulatory agent is potentially important for treatment of MS
Effect of simvastatin on evolution of experimental autoimmune encephalomyelitis in C57BL/6 mice
Gh. Mosayebi, Ph.D.+,A. Ghazavi, M.Sc,K. Ghasami, M.D.,M.A. Payani , M.Bs
Journal of Mazandaran University of Medical Sciences , 2007,
Abstract: Background and Purpose: Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme, a reductase and widely used as cholesterol-lowering agent. It is a promising candidate for future treatment in multiple sclerosis (MS), as it has been shown to exhibit immunomodulatory and anti-inflammatory effects. This study examined the effect of simvastatin on the evolution of experimental autoimmune encephalomyelitis (EAE), as an animal model for MS.Materials and Methods: EAE was induced by immunization of 8 week old C57BL/6 mice with MOG35-55 peptide with complete Freunds adjuvant. Therapy with simvastatin (1mg/kg/every day given as oral) was started on day 3 before the immunization until 25 day after immunization. Total antioxidant capacity (TAC) was assessed by ferric reducing-antioxidant power (FRAP) method. Nitric oxide (NO) production was also estimated by Griess reaction.Results: The results show that simvastatin-treated mice had significantly less incidence and clinical score of EAE than non-treated (control) EAE induced mice (p=0.001 and p=0.0001, respectively). Moreover, treated mice displayed a significantly delayed disease onset compared with control mice. Simvastatin significantly increased TAC and level serum uric acid (p=0.001), but had no effect on serum nitrite production.Conclusion: Our results suggest that simvastatin therapy may be effective in the prevention of symptomatic EAE. This resistance to encephalomyelitis may be associated with the inhibition of oxidative stress and the increase of antioxidant capacity.
Amelioration of Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice by Photobiomodulation Induced by 670 nm Light  [PDF]
Kamaldeen A. Muili, Sandeep Gopalakrishnan, Stacy L. Meyer, Janis T. Eells, Jeri-Anne Lyons
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030655
Abstract: Background The approved immunomodulatory agents for the treatment of multiple sclerosis (MS) are only partially effective. It is thought that the combination of immunomodulatory and neuroprotective strategies is necessary to prevent or reverse disease progression. Irradiation with far red/near infrared light, termed photobiomodulation, is a therapeutic approach for inflammatory and neurodegenerative diseases. Data suggests that near-infrared light functions through neuroprotective and anti-inflammatory mechanisms. We sought to investigate the clinical effect of photobiomodulation in the Experimental Autoimmune Encephalomyelitis (EAE) model of multiple sclerosis. Methodology/Principal Findings The clinical effect of photobiomodulation induced by 670 nm light was investigated in the C57BL/6 mouse model of EAE. Disease was induced with myelin oligodendrocyte glycoprotein (MOG) according to standard laboratory protocol. Mice received 670 nm light or no light treatment (sham) administered as suppression and treatment protocols. 670 nm light reduced disease severity with both protocols compared to sham treated mice. Disease amelioration was associated with down-regulation of proinflammatory cytokines (interferon-γ, tumor necrosis factor-α) and up-regulation of anti-inflammatory cytokines (IL-4, IL-10) in vitro and in vivo. Conclusion/Significance These studies document the therapeutic potential of photobiomodulation with 670 nm light in the EAE model, in part through modulation of the immune response.
Astragaloside IV Attenuates Experimental Autoimmune Encephalomyelitis of Mice by Counteracting Oxidative Stress at Multiple Levels  [PDF]
Yixin He, Min Du, Yan Gao, Hongshuai Liu, Hongwei Wang, Xiaojun Wu, Zhengtao Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076495
Abstract: Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI), a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE) in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS) as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS.
A Cannabigerol Derivative Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis  [PDF]
Francisco J. Carrillo-Salinas, Carmen Navarrete, Miriam Mecha, Ana Feliú, Juan A. Collado, Irene Cantarero, María L. Bellido, Eduardo Mu?oz, Carmen Guaza
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094733
Abstract: Phytocannabinoids that do not produce psychotropic effects are considered of special interest as novel therapeutic agents in CNS diseases. A cannabigerol quinone, the compound VCE-003, has been shown to alleviate symptoms in a viral model of multiple sclerosis (MS). Hence, we studied T cells and macrophages as targets for VCE-003 and its efficacy in an autoimmune model of MS. Proliferation, cell cycle, expression of activation markers was assessed by FACs in human primary T cells, and cytokine and chemokine production was evaluated. Transcription was studied in Jurkat cells and RAW264.7 cells were used to study the effects of VCE-003 on IL-17-induced macrophage polarization to a M1 phenotype. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG35–55) immunization and spinal cord pathology was assessed by immunohistochemistry. Neurological impairment was evaluated using disease scores. We show here that VCE-003 inhibits CD3/CD28-induced proliferation, cell cycle progression and the expression of the IL-2Rα and ICAM-1 activation markers in human primary T cells. VCE-003 inhibits the secretion of Th1/Th17 cytokines and chemokines in primary murine T cells, and it reduces the transcriptional activity of the IL-2, IL-17 and TNFα promoters induced by CD3/CD28. In addition, VCE-003 and JWH-133, a selective CB2 agonist, dampened the IL-17-induced polarization of macrophages to a pro-inflammatory M1 profile. VCE-003 also prevented LPS-induced iNOS expression in microglia. VCE-003 ameliorates the neurological defects and the severity of MOG-induced EAE in mice through CB2 and PPARγ receptor activation. A reduction in cell infiltrates, mainly CD4+ T cells, was observed, and Th1 and Th17 responses were inhibited in the spinal cord of VCE-003-treated mice, accompanied by weaker microglial activation, structural preservation of myelin sheets and reduced axonal damage. This study highlights the therapeutic potential of VCE-003 as an agent for the treatment of human immune diseases with both inflammatory and autoimmune components.
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