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CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.

ABSTRACT: To assess the effects and mechanisms of a CD200R1 agonist administered during the progressive stage of a multiple sclerosis model, we administered CD200R1 agonist (CD200Fc) or control IgG2a during the chronic phase of disease (days 10-30) in mice with experimental autoimmune encephalomyelitis (EAE), induced using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) peptide. We found that administration of CD200Fc during the chronic stages of EAE reduced disease severity, demyelination, and axonal damage, through the modulation of several key disease mechanisms. CD200Fc treatment suppressed macrophage and microglial accumulation within the CNS, in part through downregulation of adhesion molecules VLA-4 and LFA-1, which are necessary for macrophage migration. Additionally, expression of activation markers MHC-II and CD80 and production of proinflammatory cytokines IL-6, tumor necrosis factor-alpha, and nitric oxide by CD11b(+) cells were decreased in both the spleen and CNS in CD200Fc-treated animals. Antigen-presenting cell function in the spleen and CNS was suppressed in CD200Fc-treated mice, but there were no significant alterations on T cell activation or phenotype. CD200Fc increased apoptosis of CD11b(+) cells but not astrocytes. In contrast, addition of CD200Fc treatment protected oligodendrocytes from apoptosis in vitro and in vivo. Our results demonstrate that CD200R1 agonists modulate both myeloid- and non-myeloid-related mechanisms of chronic disease in the EAE model and may be effective in the treatment of progressive multiple sclerosis and other neurodegenerative diseases.

SUBMITTER: Liu Y

PROVIDER: S-EPMC2837938 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.

Liu Yingru Y Bando Yoshio Y Vargas-Lowy David D Elyaman Wassim W Khoury Samia J SJ Huang Tao T Reif Karin K Chitnis Tanuja T

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100201 6

To assess the effects and mechanisms of a CD200R1 agonist administered during the progressive stage of a multiple sclerosis model, we administered CD200R1 agonist (CD200Fc) or control IgG2a during the chronic phase of disease (days 10-30) in mice with experimental autoimmune encephalomyelitis (EAE), induced using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) peptide. We found that administration of CD200Fc during the chronic stages of EAE reduced disease severity, demyelination, a ...[more]

PMID: 20147531

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Project description:PurposeTo test if MPO-Gd, a gadolinium-based magnetic resonance (MR) imaging probe that is sensitive and specific for the proinflammatory and oxidative enzyme myeloperoxidase (MPO), which is secreted by certain inflammatory cells, is more sensitive than diethylenetriaminepentaacetic acid (DTPA)-Gd in revealing early subclinical and chronic disease activity in the brain in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis.Materials and methodsThe protocol for animal experiments was approved by the institutional animal care committee. A total of 61 female SJL mice were induced with EAE. Mice underwent MPO-Gd- or DTPA-Gd-enhanced MR imaging on days 6, 8, and 10 after induction, before clinical disease develops, and during chronic disease at remission and the first relapse. Brains were harvested at these time points for flow cytometric evaluation of immune cell subtypes and immunohistochemistry. Statistical analysis was performed, and P < .05 was considered to indicate a significant difference.ResultsMPO-Gd helps detect earlier (5.2 vs 2.3 days before symptom onset, P = .004) and more (3.1 vs 0.3, P = .008) subclinical inflammatory lesions compared with DTPA-Gd, including in cases in which there was no evidence of overt blood-brain barrier (BBB) breakdown detected with DTPA-Gd enhancement. The number of MPO-Gd-enhancing lesions correlated with early infiltration of MPO-secreting monocytes and neutrophils into the brain (r = 0.91). MPO-Gd also helped detect more lesions during subclinical disease at remission (5.5 vs 1.3, P = .006) and at the first relapse (9.0 vs 2.7, P = .03) than DTPA-Gd, which also correlated well with the presence and accumulation of MPO-secreting inflammatory cells in the brain (r = 0.93).ConclusionMPO-Gd specifically reveals lesions with inflammatory monocytes and neutrophils, which actively secrete MPO. These results demonstrate the feasibility of detection of subclinical inflammatory disease activity in vivo, which is different from overt BBB breakdown.

Project description:BackgroundMultiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.MethodsAnti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNγ)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG₃₅₋₅₅). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration.ResultsDiazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord.ConclusionTaken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.

Project description:Evolution of glomerulonephritis (GN) to tubulointerstitial disease is a universal antecedent to the development of chronic kidney disease (CKD). There is also evidence that angiotensin converting enzyme (ACE) inhibition may attenuate the development of CKD in some forms of glomerulonephritis. We tested the role of ACE inhibition in a model of GN in which complement-dependent tubulointerstitial disease develops. GN was induced in C57BL/6 mice with intraperitoneal injections of horse spleen apoferritin (HSA) using lipopolysaccharide (LPS) as an adjuvant. Four groups of six animals were studied: saline-injected control mice treated with captopril or water, and GN mice treated with captopril or water. GN developed in all HSA-treated animals. In those receiving captopril, however, proteinuria (albumin/creatinine ratio) was significantly reduced by captopril treatment. Array screening was used to examined the expression of collagen-related genes and determine if these effects could be mediated by regulation of collagen genes. Six genes were identified for further analysis by quantitative RT-PCR. This model demonstrates that tubulointerstitial disease can be attenuated by ACE inhibition, with clinical, histologic, and gene expression measures. All protocols were approved by the Institutional Animal Care and Use Committee at SUNY Upstate Medical University. We employed four groups of six mice each: saline-injected control mice with and without captopril, and GN with and without captopril. C57BL/6 mice were purchased from The Jackson Laboratories (Bar Harbor, ME). Glomerulonephritis (GN) was induced by intraperitoneal (i.p.) injection of 10 mg of apoferritin from horse spleen (HSA, Sigma, St. Louis, MO) five days per week, with i.p. injection of 100 micrograms lipopolysaccharide (LPS, from Salmonella minnesota; EMD Biosciences, La Jolla, CA), as adjuvant, three times per week. Control animals received equal volumes of 0.15 M NaCl by i.p. injection. Injections were begun when the mice were approximately eight weeks of age and were continued for six weeks. Captopril, at 100 mg/kg/day was given in the drinking water. After 9 weeks, the animals were euthanized and kidneys were removed for RNA purification and analysis.

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CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.

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CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.

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