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John R Bethea - One of the best experts on this subject based on the ideXlab platform.

  • transgenic inhibition of astroglial nf κb improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central Nervous System Inflammation
    Journal of Immunology, 2009
    Co-Authors: Roberta Brambilla, Trikaldarshi Persaud, Shaffiat Karmally, Valery I Shestopalov, Galina Dvoriantchikova, Dmitry Ivanov, Lubov Nathanson, Scott R Barnum, John R Bethea
    Abstract:

    In the CNS, the transcription factor NF-κB is a key regulator of Inflammation and secondary injury processes. Following trauma or disease, the expression of NF-κB-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-κB (glial fibrillary acidic protein-IκBα-dominant-negative mice) resulted in reduced disease severity and improved functional recovery following experimental autoimmune encephalomyelitis. At the chronic stage of the disease, transgenic mice exhibited an overall higher presence of leukocytes in spinal cord and brain, and a markedly higher percentage of CD8 + CD122 + T regulatory cells compared with wild type, which correlated with the timing of clinical recovery. We also observed that expression of proinflammatory genes in both spinal cord and cerebellum was delayed and reduced, whereas the loss of neuronal-specific molecules essential for synaptic transmission was limited compared with wild-type mice. Furthermore, death of retinal ganglion cells in affected retinas was almost abolished, suggesting the activation of neuroprotective mechanisms. Our data indicate that inhibiting NF-κB in astrocytes results in neuroprotective effects following experimental autoimmune encephalomyelitis, directly implicating astrocytes in the pathophysiology of this disease.

  • transgenic inhibition of astroglial nf kappa b improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central Nervous System Inflammation
    Journal of Immunology, 2009
    Co-Authors: Roberta Brambilla, Trikaldarshi Persaud, Shaffiat Karmally, Valery I Shestopalov, Galina Dvoriantchikova, Dmitry Ivanov, Lubov Nathanson, Scott R Barnum, John R Bethea
    Abstract:

    In the CNS, the transcription factor NF-kappaB is a key regulator of Inflammation and secondary injury processes. Following trauma or disease, the expression of NF-kappaB-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-kappaB (glial fibrillary acidic protein-IkappaB alpha-dominant-negative mice) resulted in reduced disease severity and improved functional recovery following experimental autoimmune encephalomyelitis. At the chronic stage of the disease, transgenic mice exhibited an overall higher presence of leukocytes in spinal cord and brain, and a markedly higher percentage of CD8(+)CD122(+) T regulatory cells compared with wild type, which correlated with the timing of clinical recovery. We also observed that expression of proinflammatory genes in both spinal cord and cerebellum was delayed and reduced, whereas the loss of neuronal-specific molecules essential for synaptic transmission was limited compared with wild-type mice. Furthermore, death of retinal ganglion cells in affected retinas was almost abolished, suggesting the activation of neuroprotective mechanisms. Our data indicate that inhibiting NF-kappaB in astrocytes results in neuroprotective effects following experimental autoimmune encephalomyelitis, directly implicating astrocytes in the pathophysiology of this disease.

Philippe Gasque - One of the best experts on this subject based on the ideXlab platform.

  • CD93 regulates central Nervous System Inflammation in two mouse models of autoimmune encephalomyelitis.
    Immunology, 2018
    Co-Authors: Mark R. Griffiths, Marina Botto, Bryan Paul Morgan, James W. Neal, Philippe Gasque
    Abstract:

    Microglia and non-professional immune cells (endothelial cells, neurons) participate in the recognition and removal of pathogens and tissue debris in the injured central Nervous System through major pro-inflammatory processes. However, the mechanisms involved in regulating these responses remain ill-characterized. We herein show that CD93, also known as complement C1qRp/AA4 stem cell marker, has an important role in the regulation of inflammatory processes. The role of CD93 was evaluated in two models of neuroInflammation. We used the MOG-experimental autoimmune encephalomyelitis (EAE) model and the antibody-dependent EAE (ADEAE), which were induced in wild-type and CD93 knockout mice. We found that CD93 was highly expressed by neurons, endothelial cells and microglia (ramified >> amoeboid). Astrocytes and oligodendrocytes did not to express CD93. We further observed that CD93-deficient (CD93-/- ) mice presented a more robust brain and spinal cord Inflammation in EAE and ADEAE. Encephalitis in CD93-/- was characterized by increased numbers of infiltrating M1 macrophages (CD11c+ CD206- ) and amoeboid microglia exhibiting a more activated phenotype (Tomato Lectinhigh Cox2high ). Damage to and leakage through the blood-brain barrier was increased in CD93-/- animals and was associated with a more robust neuronal injury when compared with wild-type EAE mice. We propose that CD93 is an important neuro-immune regulator to control central Nervous System Inflammation.

  • expression of the receptor for complement c5a cd88 is up regulated on reactive astrocytes microglia and endothelial cells in the inflamed human central Nervous System
    American Journal of Pathology, 1997
    Co-Authors: Philippe Gasque, J W Neal, S K Singhrao, O Gotze, B.p. Morgan
    Abstract:

    C5a receptor (C5aR, CD88) is a receptor originally described on neutrophils and monocyte-macrophages but recently found on hepatocytes, epithelial cells, endothelial cells, and tissue mast cells. We recently reported that human fetal astrocytes expressed a functional C5aR in vitro. Here we examine C5aR expression in adult brain cultures by immunostaining with six different anti-C5aRs and show that C5aR is expressed constitutively by astrocytes, microglia, and fibroblast-like cells but not by oligodendrocytes. In fetal brain cultures we confirmed that astrocytes constitutively expressed C5aR and demonstrated that fetal microglia and fibroblast-like cells but not oligodendrocytes and neurones expressed C5aR. Incubation with inflammatory cytokines (interferon gamma, interleukin-1, and tumor necrosis factor alpha) or phorbol ester failed to induce or up-regulate C5aR expression on fetal or adult brain cells. Immunohistochemistry was performed to determine the expression and distribution of C5aR in the normal and inflamed brain. In the normal brain C5aR was minimally expressed, whereas in inflamed brains from a variety of pathologies, C5aR expression was greatly up-regulated on reactive astrocytes and microglia and to a lesser extent on endothelial cells. We propose that expression of C5aR is a marker of central Nervous System Inflammation, and that C5aR expression on brain cells in Inflammation plays an important role in cell activation and recruitment (gliosis).

Monique Touret - One of the best experts on this subject based on the ideXlab platform.

  • neuromyelitis optica study model based on chronic infusion of autoantibodies in rat cerebrospinal fluid
    Journal of Neuroinflammation, 2016
    Co-Authors: Romain Marignier, Anne Ruiz, Sylvie Cavagna, A Nicole, Chantal Watrin, Monique Touret
    Abstract:

    Background Devic’s neuromyelitis optica (NMO) is an autoimmune astrocytopathy, associated with central Nervous System Inflammation, demyelination, and neuronal injury. Several studies confirmed that autoantibodies directed against aquaporin-4 (AQP4-IgG) are relevant in the pathogenesis of NMO, mainly through complement-dependent toxicity leading to astrocyte death. However, the effect of the autoantibody per se and the exact role of intrathecal AQP4-IgG are still controversial.

Lior Mayo - One of the best experts on this subject based on the ideXlab platform.

  • il 10 dependent tr1 cells attenuate astrocyte activation and ameliorate chronic central Nervous System Inflammation
    Brain, 2016
    Co-Authors: Lior Mayo, Andre Pires Da Cunha, Asaf Madi, Vanessa Beynon, Zhiping Yang, Jorge Ivan Alvarez, Alexandre Prat, Raymond A Sobel
    Abstract:

    SEE WINGER AND ZAMVIL DOI101093/BRAIN/AWW121 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The innate immune System plays a central role in the chronic central Nervous System Inflammation that drives neurological disability in progressive forms of multiple sclerosis, for which there are no effective treatments. The mucosal immune System is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells. Here we report that nasal administration of CD3-specific antibody ameliorates disease in a progressive animal model of multiple sclerosis. This effect is IL-10-dependent and is mediated by the induction of regulatory T cells that share a similar transcriptional profile to Tr1 regulatory cells and that suppress the astrocyte inflammatory transcriptional program. Treatment results in an attenuated inflammatory milieu in the central Nervous System, decreased microglia activation, reduced recruitment of peripheral monocytes, stabilization of the blood-brain barrier and less neurodegeneration. These findings suggest a new therapeutic approach for the treatment of progressive forms of multiple sclerosis and potentially other types of chronic central Nervous System Inflammation.

  • type i interferons and microbial metabolites of tryptophan modulate astrocyte activity and central Nervous System Inflammation via the aryl hydrocarbon receptor
    Nature Medicine, 2016
    Co-Authors: Veit Rothhammer, Lior Mayo, Jessica E Kenison, Ivan D Mascanfroni, Lukas Bunse, Maisa C Takenaka, Chuncheih Chao, Bonny Patel, Manon Blain, Jorge Ivan Alvarez
    Abstract:

    After upregulation of AHR in astrocytes by type I interferons, commensal-microbe-derived metabolites of dietary tryptophan act on astrocytes to suppress CNS Inflammation.

John J Bright - One of the best experts on this subject based on the ideXlab platform.

  • peroxisome proliferator activated receptor gamma agonists inhibit experimental allergic encephalomyelitis by blocking il 12 production il 12 signaling and th1 differentiation
    Genes and Immunity, 2002
    Co-Authors: Chandramohan Natarajan, John J Bright
    Abstract:

    Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor transcription factor that regulates adipocyte differentiation and glucose homeostasis. PPARgamma agonists are potent therapeutic agents for the treatment of type 2 diabetes and obesity. PPARgamma agonists also prevent Inflammation in animal models, suggesting their use for the treatment of human inflammatory diseases. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating disease model of multiple sclerosis (MS) and IL-12 plays a crucial role in the pathogenesis of EAE and MS. In this study we have examined the effect of PPARgamma agonists on the pathogenesis of EAE. In vivo treatment of SJL/J mice with PPARgamma agonists, 15-deoxydelta(12,14) prostaglandin J2 or Ciglitazone, decreased the duration and clinical severity of active immunization and adoptive transfer models of EAE. PPARgamma agonists inhibited EAE in association with a decrease in IL-12 production and differentiation of neural antigen-specific Th1 cells. In vitro treatment of activated T cells with PPARgamma agonists inhibited IL-12-induced activation of JAK-STAT signaling pathway and Th1 differentiation. These findings highlight the fact that PPARgamma agonists regulate central Nervous System Inflammation and demyelination by inhibiting IL-12 production, IL-12 signaling and Th1 differentiation in EAE.