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Inducible nitric oxide synthase deficiency leads to early and severe demyelination in a murine coronavirus induced disease model of multiple sclerosis
Multiple Sclerosis Journal ; 28(3 Supplement):749-750, 2022.
Article in English | EMBASE | ID: covidwho-2138805
ABSTRACT

Introduction:

Inducible nitric oxide synthase (iNOS) catalyses production of nitric oxide during an inflammatory stimuli and is a signature marker of M1-like microglia/macrophages. iNOS mRNA and protein were found in brain lesions of MS patients however its role in demyelination remains unclear. We employed RSA59, a mild hepatoneurotropic strain of Mouse hepatitis virus (MHV) which in 4-weeks-old C57BL/6 mice causes biphasic CNS disease characterised by acute neuroinflammation (day5 p.i.) and chronic demyelination and axonal loss (day30 p.i.). Microglia/ macrophages are central to the disease pathology and require assistance from infiltrating CD4+ T cells to mount protective host immune response. The CNS immune interactions during the acute-adaptive transition stage thus determine disease trajectory. Objective(s) To understand the role of iNOS in microglia/macrophage and peripheral T cell communication and assess its effect on demyelination. Aim(s) To study the role of iNOS in demyelination. Method(s) 4-5-weeks-old MHV-free wildtype C57BL/6 (WT) and iNOS knockout (iNOS-/-) mice were infected intracranially with 20000 or 10000 pfus of RSA59 and assessed daily for weight loss and disease score. Mice were sacrificed at day9/10 and day30 p.i. CNS viral titers were detected by plaque assay. Transcript levels of anti-inflammatory and phagocytic M2-like phenotype markers were analysed by qRT PCR. Differential CNS immune cell infiltration was assessed by flow cytometry. LFB and Iba1 staining was used to study demyelination and microglia/macrophage activation in the CNS. Result(s) iNOS-/- mice infected with RSA59 at 20000 pfus exhibited aggravated disease and high mortality at the acute-adaptive transition stage i.e., day9/10 p.i. as compared to wildtype controls despite being no differences in virus clearance by the CNS. Histopathology at this stage showed early demyelination in the spinal cords accompanied by presence of amoeboid microglia macrophages;high CNS mRNA expression of M2-like phenotype markers, TGFbeta, Arg1, CD206 and TREM2;and more infiltration of T regulatory cells. iNOS-/- mice infected at low pfus of virus i.e., 10000 also showed significantly more chronic demyelination at day30 p.i. Conclusion(s) Our studies reveal a protective role of iNOS against RSA59 induced demyelination by regulating the CNS inflammatory phenotype specifically the phenotypic transition of microglia/macrophages and thereby their interaction with peripheral immune cells.
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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Multiple Sclerosis Journal Year: 2022 Document Type: Article

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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Multiple Sclerosis Journal Year: 2022 Document Type: Article