CD40L protects against mouse hepatitis virus-induced neuroinflammatory demyelination

Saadi, Fareeha; Chakravarty, Debanjana; Kumar, Saurav; Kamble, Mithila; Saha, Bhaskar; Shindler, Kenneth S.; Sarma, Jayasri Das

doi:10.1371/journal.ppat.1010059

Cited by 13 publications

(36 citation statements)

References 72 publications

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“…CD40-CD40L dyad is an important immune dyad that controls both CD4 + T cell and microglia functions [87,88]. Our studies in CD40L −/− mice showed that the absence of CD40L renders mice highly susceptible to RSA59 infection due to reduced microglia/macrophage activation during the acute phase of infection required to eliminate the virus (Figures 5) [89]. Effector CD4 + T recruitment to the CNS is significantly dampened, and due to the [30].…”

Section: Overview Of Microglial Activation In Encephalomyelitis: Ampl...mentioning

confidence: 90%

Neurotropic Virus-Induced Meningoencephalomyelitis

Saadi¹,

Chakravarty²,

Kasle³

et al. 2022

RNA Viruses Infection

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Meningoencephalomyelitis emanates under the umbrella relating inflammatory changes of the Central Nervous System (CNS). Meningitis denotes inflammation in the meningeal layers, encephalitis is an acute diffuse inflammation of the brain, and inflammation in the spinal cord is denoted as myelitis. These can be interrelated or independent of each other depending on the etiology. The entire mechanism of meningoencephalomyelitis is governed by an acute innate inflammatory branch followed by a chronic progressive, adaptive branch of immunity with clinical signs like hyperthermia, weight loss, hypoxia, leukocytosis. This book chapter will focus on viral-induced meningitis, encephalitis, and myelitis. Thirty years of experience working with a murine-β-coronavirus (m-CoV); Mouse hepatitis virus (MHV)-A59 induced experimental model system provided us a thorough understanding of neuroglial cell-mediated acute neuroinflammation, denoted by the accumulation of leukocyte-common-antigen (LCA) positive or CD45+ leukocytes in perivascular infiltrates referred to as perivascular cuff formation and microglial nodules in the brain parenchyma, which mimics specific pathology of human neurological disease multiple sclerosis (MS). Additionally, in this chapter, we summarized the role of CNS resident microglial activation and its interaction with peripheral migratory T cells in mounting neuropathogenesis and host immunity in different families of neurotrophic encephalomyelitis viruses that cause CNS inflammation.

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Section: Overview Of Microglial Activation In Encephalomyelitis: Ampl...mentioning

confidence: 90%

Neurotropic Virus-Induced Meningoencephalomyelitis

Saadi¹,

Chakravarty²,

Kasle³

et al. 2022

RNA Viruses Infection

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“…TAMs were under the intense discussion for decades due to high heterogeneity and various functions in different cancer models [30,31]. Appearing cell markers for TAMs, such as CD206, PM-2K, CD40, COX2 and CCR2, led to deeper investigations of tumor associated macrophages [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Immunoprofiling in Breast Cancer Microenvironment with Multiplexed Immunofluorescence

Yang

Dong

et al. 2022

Preprint

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Background The immunoprofiles in tumor microenvironment (TME) has established impacts on the tumorigenesis, metastasis, therapy sensitivity and prognosis in various solid tumors, including breast cancer. Regulation of local immune cell homeostasis is considered as a promising strategy for breast cancer therapy. Aim Comprehensively investigate the landscape of tumor-infiltrated immune cells in breast cancer and benign tissues, and provide novel evidence for potential immunotherapy strategies. Method A total of 140 pairs of breast cancer and benign tissues were collected and sectioned. The multiplexed immunofluorescence was applied to simultaneously analyze the immunoprofiles in breast cancer TME. Images were captured by AKOYA-Vectra 3 and analyzed with InForm 2.1 software. Results Comparing the general benign with malignant samples, the mean percentages of T cells (17.03% vs 14.85%, p=0.2329), B cells (6.406% vs 3.763%, p=0.0189), and macrophages (17.06% vs 27.1%, p=0.008) showed dramatic difference. In addition, we compared segmental areas, para-cancer with cancer tissues, different pathological and molecular types, and found that the main difference was the proportion of macrophages, especially the M2 subtype. Conclusion Macrophages and M2 subtype were the iconic differentiated infiltrating immune cells in breast cancer, especially related with the malignancy, clinic stages and tumorigenesis, which was the promising target in cancer therapy.

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“…iNOS knockout or inhibition, in turn, resulted in Treg induction [43]. Studies in mice deficient in CD4+ T cells, Ifit2 or CD40L have shown that the CD4+ T cells are protective and crucial for MG/Mφ homeostasis during RSA59 infection [27][28][29]. Though the virus clearance remains unaffected, whether the increase in the numbers of Tregs affects the functions of effector T cells in infected iNOS deficient mice remains to be checked.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in the neurotoxicant cuprizone-induced demyelination model, on the other hand, showed that the absence of iNOS exacerbated demyelination at early time points [17]. We have previously reported the central role of microglia/macrophage in demyelination and the protective role of CD4+ T cells and its ligand CD40L through its interaction with microglia/macrophage in MHV-RSA59 induced neuroinflammatory disease [27, 29]. iNOS has been reported to be induced in BV-2 microglial cells on ligation of CD40 [30].…”

Section: Discussionmentioning

confidence: 99%

“…This was attributed to the reduced activation and antigen presentation by microglia/ macrophage at the acute phase resulting in lower priming of CD4+ T cells in the cervical lymph nodes and reduced infiltration in the brain at day 10 p.i. Thus, leading to virus persistence and exacerbated chronic phase demyelination in the CD40L-/- mice mediated by phagocytic amoeboid microglia/ macrophages [29]. Studies have shown that CD40L binding to CD40R on microglia induces the production of iNOS [30]; we, therefore, wanted to examine the role of iNOS in RSA59 induced neuroinflammation comparing iNOS depleted mice in the background of demyelination susceptible C57BL/6 mice (iNOS-/-) and wild type C57BL/6 mice (WT) in this study to delve deeper into our understanding of CD4+ T cell and MG/Mφ crosstalk.…”

Section: Introductionmentioning

confidence: 99%

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Inducible Nitric Oxide Synthase deficiency leads to early demyelination by altering the balance between pro- and anti-inflammatory responses against Murine-β-Coronavirus

Kamble

Saadi

Kumar

et al. 2022

Preprint

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The neurological disease Multiple sclerosis (MS) is characterized by neuroinflammation and demyelination orchestrated by the activated glial cells, the CNS infiltrating leukocytes, and their reciprocal interaction through inflammatory signals. Inducible nitric oxide synthase (iNOS), an enzyme that catalyzes sustained nitric oxide production in response to an inflammatory stimulus, is a pro-inflammatory marker expressed particularly by the microglia/macrophages (MG/Mϕ) during neuroinflammation. In MS, iNOS has been reportedly associated with the disease pathology; however, studies dissecting its role in the underlying mechanisms, specifically demyelination, are limited. Therefore, we studied the role of iNOS in a recombinant beta-coronavirus- MHV-RSA59- induced neuroinflammation, which is a prototypic animal model used to investigate the pathological hallmarks of MS, neuroinflammatory demyelination, and axonal degeneration. During the acute phase of infection with RSA59, wildtype C57BL/6 (WT) mice had significantly upregulated iNOS expression in macrophages, natural killer cells, and natural killer T cells suggesting a role for iNOS in RSA59-induced neuroinflammation. Studies comparing RSA59-infected WT and iNOS-deficient mice revealed that iNOS deficiency aggravated the disease with increased CNS infiltration of macrophages and neutrophils and enhanced mortality. As early as 9-10 days after the infection, the CNS of iNOS-deficient mice had substantially higher demyelination marked with morphologically defined MG/Mϕ in the demyelinating regions. Transcript analysis confirmed the significant upregulation of type2 macrophage (M2) markers- Arginase 1, CD206, and TREM2- in the CNS of iNOS-deficient mice. Corroborating to the phenotype, the iNOS-deficient mice showed a significantly higher expression of TGFβ- an anti-inflammatory cytokine- and increased T regulatory (Treg) cell infiltration, indicating an anti-inflammatory milieu established early after the infection. These observations highlight a protective role of iNOS in virus-induced neuroinflammation whereas its absence leads to MG/Mϕ polarization towards a phenotype that may be involved in the exacerbated demyelination pathology.

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CD40L protects against mouse hepatitis virus-induced neuroinflammatory demyelination

Cited by 13 publications

References 72 publications

Neurotropic Virus-Induced Meningoencephalomyelitis

Neurotropic Virus-Induced Meningoencephalomyelitis

Immunoprofiling in Breast Cancer Microenvironment with Multiplexed Immunofluorescence

Inducible Nitric Oxide Synthase deficiency leads to early demyelination by altering the balance between pro- and anti-inflammatory responses against Murine-β-Coronavirus

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