Neuronal NF-κB ablation does not influence neuro-axonal degeneration in experimental autoimmune demyelination

Vision impairment due to optic neuritis (ON) is one of the major clinical presentations in Multiple Sclerosis (MS) and is characterized by inflammation and degeneration of the optic nerve and retina. Currently available treatments are only partially effective and have a limited impact on the neuroinflammatory pathology of the disease. A recent study from our laboratory highlighted the beneficial effect of arginase 2 (A2) deletion in suppressing retinal neurodegeneration and inflammation in an experimental model of MS. Utilizing the same model, the present study investigated the impact of A2 deficiency on MS-induced optic neuritis. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2-/-) mice. EAE-induced cellular infiltration, as well as activation of microglia and macrophages, were reduced in A2-/- optic nerves. Axonal degeneration and demyelination seen in EAE optic nerves were observed to be reduced with A2 deletion. Further, the lack of A2 significantly ameliorated astrogliosis induced by EAE. In conclusion, our findings demonstrate a critical involvement of arginase 2 in mediating neuroinflammation in optic neuritis and suggest the potential of A2 blockade as a targeted therapy for MS-induced optic neuritis.

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Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE

10.1101/2020.12.20.423638 ◽

2020 ◽

Author(s):

P Chaudhary ◽

GH Marracci ◽

E Calkins ◽

E Pocius ◽

AL Bensen ◽

...

Keyword(s):

Thyroid Hormone ◽

Axonal Degeneration ◽

List Type ◽

Protective Effects ◽

Autoimmune Encephalomyelitis ◽

Thyroid Receptor ◽

Oligodendrocyte Precursor ◽

Receptor Beta ◽

Experimental Autoimmune ◽

Degenerating Axons

AbstractWe have previously demonstrated that thyromimetics stimulate oligodendrocyte precursor cell differentiation and promote remyelination in murine demyelination models. We investigated whether a thyroid receptor-beta selective thyromimetic, sobetirome (Sob), and its CNS-targeted prodrug, Sob-AM2, could prevent myelin and axonal degeneration in experimental autoimmune encephalomyelitis (EAE). Compared to controls, EAE mice receiving triiodothyronine (T3, 0.4mg/kg), Sob (5mg/kg) or Sob-AM2 (5mg/kg) had reduced clinical disease and, within the spinal cord, less tissue damage, more normally myelinated axons, fewer degenerating axons and more oligodendrocytes. T3 and Sob also protected cultured oligodendrocytes against cell death. Thyromimetics thus might protect against oligodendrocyte death, demyelination and axonal degeneration as well as stimulate remyelination in multiple sclerosis.HighlightsThyroid hormone, the thyromimetic Sob and its CNS penetrating prodrug, Sob-AM2, reduce disease severity, reduce myelin and axonal degeneration and protect oligodendrocytes in EAE.The benefits of Sob and Sob-AM2 may be via direct protective effects on oligodendrocytes and reduction in activity of microglia/macrophages.

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Differential roles of microglia and monocytes in the inflamed central nervous system

Journal of Experimental Medicine ◽

10.1084/jem.20132477 ◽

2014 ◽

Vol 211 (8) ◽

pp. 1533-1549 ◽

Cited By ~ 446

Author(s):

Ryo Yamasaki ◽

Haiyan Lu ◽

Oleg Butovsky ◽

Nobuhiko Ohno ◽

Anna M. Rietsch ◽

...

Keyword(s):

Tissue Injury ◽

Expression Profiles ◽

Disease Onset ◽

Gene Expression Profiles ◽

Autoimmune Encephalomyelitis ◽

Block Face ◽

Human Disorder ◽

Autoimmune Demyelination ◽

New Strategies ◽

Experimental Autoimmune

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell–mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.

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The Th17–ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease

Journal of Experimental Medicine ◽

10.1084/jem.20072404 ◽

2008 ◽

Vol 205 (4) ◽

pp. 811-823 ◽

Cited By ~ 187

Author(s):

Thaddeus Carlson ◽

Mark Kroenke ◽

Praveen Rao ◽

Thomas E. Lane ◽

Benjamin Segal

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Th17 Cells ◽

Polymorphonuclear Leukocytes ◽

Autoimmune Encephalomyelitis ◽

Cxc Chemokine ◽

The Central Nervous System ◽

Autoimmune Demyelination ◽

Clinical Deficits ◽

Experimental Autoimmune

The ELR+ CXC chemokines CXCL1 and CXCL2 are up-regulated in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, their functional significance and the pathways regulating their expression are largely unknown. We show that transfer of encephalitogenic CD4+ Th17 cells is sufficient to induce CXCL1 and CXCL2 transcription in the spinal cords of naive, syngeneic recipients. Blockade or genetic silencing of CXCR2, a major receptor for these chemokines in mice, abrogates blood–brain barrier (BBB) breakdown, CNS infiltration by leukocytes, and the development of clinical deficits during the presentation as well as relapses of EAE. Depletion of circulating polymorphonuclear leukocytes (PMN) had a similar therapeutic effect. Furthermore, injection of CXCR2+ PMN into CXCR2−/− mice was sufficient to restore susceptibility to EAE. Our findings reveal that a Th17–ELR+ CXC chemokine pathway is critical for granulocyte mobilization, BBB compromise, and the clinical manifestation of autoimmune demyelination in myelin peptide–sensitized mice, and suggest new therapeutic targets for diseases such as MS.

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Beneficial or Harmful Role of Macrophages in Guillain-Barré Syndrome and Experimental Autoimmune Neuritis

Mediators of Inflammation ◽

10.1155/2018/4286364 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Donghui Shen ◽

Fengna Chu ◽

Yue Lang ◽

Yunlong Geng ◽

Xiangyu Zheng ◽

...

Keyword(s):

Macrophage Polarization ◽

Critical Role ◽

Decisive Role ◽

Guillain Barre Syndrome ◽

Experimental Autoimmune Neuritis ◽

Guillain Barré Syndrome ◽

Anti Inflammatory ◽

Autoimmune Demyelination ◽

Guillain Barré ◽

Experimental Autoimmune

Guillain-Barré syndrome (GBS), an immune-mediated demyelinating peripheral neuropathy, is characterized by acute weakness of the extremities and areflexia or hyporeflexia. Experimental autoimmune neuritis (EAN) is a common animal model for GBS, which represents a CD4+ T cell-mediated inflammatory autoimmune demyelination of the peripheral nervous system (PNS), and is used to investigate the pathogenic mechanism of GBS. It has been found that macrophages play a critical role in the pathogenesis of both GBS and EAN. Macrophages have been primarily classified into two major phenotypes: proinflammatory macrophages (M1) and anti-inflammatory macrophages (M2). The two different macrophage subsets M1 and M2 may play a decisive role in initiation and development of GBS and EAN. However, recently, it has been indicated that the roles of macrophages in immune regulation and autoimmune diseases are more complex than those suggested by a simple M1-M2 dichotomy. Macrophages might exert either inflammatory or anti-inflammatory effect by secreting pro- or anti-inflammatory cytokines, and either inducing the activation of T cells to mediate immune response, resulting in inflammation and demyelination in the PNS, or promoting disease recovery. In this review, we summarize the dual roles of macrophages in GBS and EAN and explore the mechanism of macrophage polarization to provide a potential therapeutic approach for GBS in the future.

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Neurofilament Protein as a Potential Biomarker of Axonal Degeneration in Experimental Autoimmune Encephalomyelitis

Neurology India ◽

10.4103/0028-3886.280651 ◽

2020 ◽

Vol 68 (2) ◽

pp. 364

Author(s):

Pin Wang ◽

LuL Jiang ◽

Cunfu Wang ◽

Zhengyu Zhu ◽

Chao Lai

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Axonal Degeneration ◽

Neurofilament Protein ◽

Autoimmune Encephalomyelitis ◽

Potential Biomarker ◽

Experimental Autoimmune

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A Clonal NG2-Glia Cell Response in a Mouse Model of Multiple Sclerosis

Cells ◽

10.3390/cells9051279 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1279 ◽

Cited By ~ 3

Author(s):

Sonsoles Barriola ◽

Fernando Pérez-Cerdá ◽

Carlos Matute ◽

Ana Bribián ◽

Laura López-Mascaraque

Keyword(s):

Multiple Sclerosis ◽

Brain Damage ◽

Tissue Repair ◽

Phenotypic Diversity ◽

Demyelinating Diseases ◽

Autoimmune Encephalomyelitis ◽

Oligodendrocyte Precursor ◽

Autoimmune Demyelination ◽

The Brain ◽

Experimental Autoimmune

NG2-glia, also known as oligodendrocyte precursor cells (OPCs), have the potential to generate new mature oligodendrocytes and thus, to contribute to tissue repair in demyelinating diseases like multiple sclerosis (MS). Once activated in response to brain damage, NG2-glial cells proliferate, and they acquire a reactive phenotype and a heterogeneous appearance. Here, we set out to investigate the distribution and phenotypic diversity of NG2-glia relative to their ontogenic origin, and whether there is a clonal NG2-glial response to lesion in an experimental autoimmune encephalomyelitis (EAE) murine model of MS. As such, we performed in utero electroporation of the genomic lineage tracer, StarTrack, to follow the fate of NG2-glia derived from single progenitors and to evaluate their response to brain damage after EAE induction. We then analyzed the dispersion of the NG2-glia derived clonally from single pallial progenitors in the brain of EAE mice. In addition, we examined several morphological parameters to assess the degree of NG2-glia reactivity in clonally-related cells. Our results reveal the heterogeneity of these progenitors and their cell progeny in a scenario of autoimmune demyelination, revealing the ontogenic phenomena at play in these processes.

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IL-12p35-Deficient Mice Are Susceptible to Experimental Autoimmune Encephalomyelitis: Evidence for Redundancy in the IL-12 System in the Induction of Central Nervous System Autoimmune Demyelination

The Journal of Immunology ◽

10.4049/jimmunol.169.12.7104 ◽

2002 ◽

Vol 169 (12) ◽

pp. 7104-7110 ◽

Cited By ~ 271

Author(s):

Bruno Gran ◽

Guang-Xian Zhang ◽

Shuo Yu ◽

Jifen Li ◽

Xiao-Han Chen ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Experimental Autoimmune Encephalomyelitis ◽

Autoimmune Encephalomyelitis ◽

Autoimmune Demyelination ◽

Deficient Mice ◽

Experimental Autoimmune

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Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway

Journal of Neuroinflammation ◽

10.1186/s12974-021-02193-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Ruo-Nan Duan ◽

Chun-Lin Yang ◽

Tong Du ◽

Ai Liu ◽

An-Ran Wang ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Immune System ◽

Experimental Autoimmune Encephalomyelitis ◽

Western Blot ◽

Blot Analysis ◽

Western Blot Analysis ◽

Autoimmune Encephalomyelitis ◽

Autoimmune Demyelination ◽

Experimental Autoimmune

Abstract Background Experimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE. Methods C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to establish the EAE model. Clinical signs were recorded and pathogenesis was investigated after immunization. CNS tissues were analyzed by immunostaining, quantitative polymerase chain reaction (qPCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Single-cell analysis was carried out in the cortices and hippocampus. Splenic and lymph node cells were evaluated with flow cytometry, qPCR, and western blot analysis. Results Here, we showed that partial Smek1 deficiency caused more severe symptoms in the EAE model than in controls by activating myeloid cells and that Smek1 was required for maintaining immunosuppressive function by modulating the indoleamine 2,3-dioxygenase (IDO1)-aryl hydrocarbon receptor (AhR) pathway. Single-cell sequencing and an in vitro study showed that Smek1-deficient microglia and macrophages were preactivated at steady state. After MOG35-55 immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1β in Smek1-/+ mice at the peak stage. Moreover, dysfunction of the IDO1-AhR pathway resulted from the reduction of interferon γ (IFN-γ), enhanced antigen presentation ability, and inhibition of anti-inflammatory processes in Smek1-/+ EAE mice. Conclusions The present study suggests a protective role of Smek1 in autoimmune demyelination pathogenesis via immune suppression and inflammation regulation in both the immune system and the central nervous system. Our findings provide an instructive basis for the roles of Smek1 in EAE and broaden the understanding of the genetic factors involved in the pathogenesis of autoimmune demyelination.

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