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Reelin depletion protects against autoimmune encephalomyelitis by decreasing vascular adhesion of leukocytes.

ABSTRACT: Neuroinflammation as a result of immune cell recruitment into the central nervous system (CNS) is a key pathogenic mechanism of multiple sclerosis (MS). However, current anti-inflammatory interventions depleting immune cells or directly targeting their trafficking into the CNS can have serious side effects, highlighting a need for better immunomodulatory strategies. We detected increased Reelin concentrations in the serum of patients with MS, resulting in increased endothelial permeability to leukocytes through increased nuclear factor κB-mediated expression of vascular adhesion molecules. We thus investigated the prophylactic and therapeutic potential of Reelin immunodepletion in experimental autoimmune encephalomyelitis (EAE) and further validated the results in Reelin knockout mice. Removal of plasma Reelin by either approach protected against neuroinflammation and largely abolished the neurological consequences by reducing endothelial permeability and immune cell accumulation in the CNS. Our findings suggest Reelin depletion as a therapeutic approach with an inherent good safety margin for the treatment of MS and other diseases where leukocyte extravasation is a major driver of pathogenicity.

SUBMITTER: Calvier L

PROVIDER: S-EPMC7860587 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Reelin depletion protects against autoimmune encephalomyelitis by decreasing vascular adhesion of leukocytes.

Calvier Laurent L Demuth Guillaume G Manouchehri Navid N Wong Connie C Sacharidou Anastasia A Mineo Chieko C Shaul Philip W PW Monson Nancy L NL Kounnas Maria Z MZ Stüve Olaf O Herz Joachim J

Science translational medicine 20200801 556

Neuroinflammation as a result of immune cell recruitment into the central nervous system (CNS) is a key pathogenic mechanism of multiple sclerosis (MS). However, current anti-inflammatory interventions depleting immune cells or directly targeting their trafficking into the CNS can have serious side effects, highlighting a need for better immunomodulatory strategies. We detected increased Reelin concentrations in the serum of patients with MS, resulting in increased endothelial permeability to le ...[more]

PMID: 32801146

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Project description:Background/Aims:Increasing evidence have associated mitochondrial dysfunction and reactive oxygen species (ROS) generation to neuron loss in multiple sclerosis (MS). PGC-1α regulates mitochondrial biogenesis and respiration and plays a pivotal role in modulating ROS levels. Here, we investigated the potential function of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) in the mammalian MS disease model, EAE experimental autoimmune encephalomyelitis (EAE). Methods:We used WT mice to evaluate the change of PGC during the course of EAE. The transgenic mice with neuron-specific overexpression of PGC-1α was applied to explore how PGC1 in neuron affects EAE outcome. A neuronal cell line of lentivirus transfection leading to PGC-1α markedly increased was applied to verify the protective effects of PGC1 in neurons. RNA-seq was employed to explore the potential target genes and signaling pathways. Results: We observed that PGC-1α were decreased at 13d, continuously decreased at 20d, then mildly increased at 30d in wild-type (WT) EAE mice, which is accompanied with alterations of mitochondrial antioxidants SOD2, Prx3, Trx2 and UCP4,5. Our study revealed that PGC-1αf/f Eno2-Cre mice improved EAE clinical symptoms, ameliorated inflammation and demyelination in spinal cords, increased mitochondrial antioxidants SOD2, Prx3, Trx2 and UCPs, reduced the production of ROS and inhibited the apoptotic pathways. In addition, PGC-1αf/f Eno2-Cre mice showed decreased apoptotic neurons compared with the WT EAE mice. In vitro, overexpressing PGC-1α by lentivirus transfection revealed similar results with that of in vivo by using NSC-34 cells treated with 1mg/ml lipopolysaccharide (LPS). Furthermore, RNA-seq analysis showed that apoptotic processes were significantly enriched in the top 10 significant GO terms of differentially expressed (DE) gene and apotosis pathway was significantly enriched in KEGG pathway analysis. Conclusion: Taken together, our findings indicate that upregulation of neuronal PGC-1α protected neuron apotosis in EAE and in vitro.

Dataset Information

Reelin depletion protects against autoimmune encephalomyelitis by decreasing vascular adhesion of leukocytes.

Publications

Reelin depletion protects against autoimmune encephalomyelitis by decreasing vascular adhesion of leukocytes.

Similar Datasets

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