Protective Effects on Central Nervous System by Acidic Polysaccharide of Panax ginseng in Relapse-Remitting Experimental Autoimmune Encephalomyelitis-Induced SJL/J Mice

Bearing pathologic and clinical similarities to human multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) is used as a murine model to test potential therapeutic agents for MS. Recently, we reported the protective effects of an acidic polysaccharide of Panax ginseng (APG) in C57BL/6 strain-dependent EAE, a model of primary progressive MS. In this study, we extend our previous findings on the therapeutic capacity of APG in relapsing-remitting EAE (rr-EAE), the animal model to closely mimic recurrent inflammatory demyelination lesions of relapsing-remitting MS. Treatments with APG led to a significant reduction of clinical symptoms and the relapse rate of EAE than vehicle treatments. Consistent with this, histological examination revealed that APG markedly modulated the infiltration of CD4[Formula: see text] T cells and CD11b[Formula: see text] macrophages into the spinal cord and the APG-treated CNS was devoid of demyelination and axonal damages. In addition, APG decreased the proliferation of peripheral PLP-reactive T cells and the production of pro-inflammatory factors such as IFN-[Formula: see text], IL-17 and TNF-[Formula: see text]. The fact that APG can induce clinically beneficial effects to distinct types of EAE furthers our understanding on the basis of its immunosuppression in EAE and, possibly, in MS. Our results suggest that APG may serve as a new therapeutic agent for MS as well as other human autoimmune diseases, and warrants continued evaluation for its translation into therapeutic application.

Download Full-text

Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11–mediated protection of regulatory T cells

Science Signaling ◽

10.1126/scisignal.aar8278 ◽

2018 ◽

Vol 11 (558) ◽

pp. eaar8278 ◽

Cited By ~ 11

Author(s):

Susanta Mondal ◽

Malabendu Jana ◽

Sridevi Dasarathi ◽

Avik Roy ◽

Kalipada Pahan

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Experimental Autoimmune Encephalomyelitis ◽

Clinical Symptoms ◽

Interleukin 4 ◽

T Helper 17 ◽

Autoimmune Encephalomyelitis ◽

Relapsing Remitting ◽

The Central Nervous System ◽

Experimental Autoimmune

Multiple sclerosis (MS) is a human disease that results from autoimmune T cells targeting myelin protein that is expressed within the central nervous system. In MS, the number of FoxP3-expressing regulatory T cells (Tregs) is reduced, which facilitates the activation of autoreactive T cells. Because aspirin (acetylsalicylic acid) is the most widely used nonsteroidal anti-inflammatory drug, we examined its immunomodulatory effect in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found that low-dose aspirin suppressed the clinical symptoms of EAE in mouse models of both relapsing-remitting and chronic disease. Aspirin reduced the development of EAE driven by myelin basic protein (MBP)–specific T cells and the associated perivascular cuffing, inflammation, and demyelination. The effects of aspirin required the presence of CD25+FoxP3+ Tregs. Aspirin increased the amounts of Foxp3 and interleukin-4 (IL-4) in T cells and suppressed the differentiation of naïve T cells into T helper 17 (TH17) and TH1 cells. Aspirin also increased the transcription of Il11 mediated by the transcription factor CREB, which was necessary for the generation of Tregs. Neutralization of IL-11 negated the effects of aspirin on Treg development and exacerbated EAE. Furthermore, we found that IL-11 alone was sufficient to maintain the percentage of FoxP3+ Tregs and protect mice from EAE. These results identify a previously uncharacterized mode of action of aspirin.

Download Full-text

An acidic polysaccharide of Panax ginseng ameliorates experimental autoimmune encephalomyelitis and induces regulatory T cells

Immunology Letters ◽

10.1016/j.imlet.2011.04.005 ◽

2011 ◽

Vol 138 (2) ◽

pp. 169-178 ◽

Cited By ~ 39

Author(s):

Insun Hwang ◽

Ginnae Ahn ◽

Eunjin Park ◽

Danbee Ha ◽

Jie-Young Song ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Experimental Autoimmune Encephalomyelitis ◽

Panax Ginseng ◽

Autoimmune Encephalomyelitis ◽

Acidic Polysaccharide ◽

Experimental Autoimmune

Download Full-text

Sex-Specific Effects of Microglia-Like Cell Engraftment during Experimental Autoimmune Encephalomyelitis

International Journal of Molecular Sciences ◽

10.3390/ijms21186824 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6824 ◽

Cited By ~ 2

Author(s):

Jinming Han ◽

Keying Zhu ◽

Kai Zhou ◽

Ramil Hakim ◽

Sreenivasa Raghavan Sankavaram ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Immune Cell ◽

Clinical Symptoms ◽

Active Immunization ◽

Inflammatory Factors ◽

Male Mice ◽

Autoimmune Encephalomyelitis ◽

Cell Engraftment ◽

Peripheral Monocyte ◽

Experimental Autoimmune

Multiple sclerosis (MS) is a chronic neuroinflammatory disorder of the central nervous system (CNS) that usually presents in young adults and predominantly in females. Microglia, a major resident immune cell in the CNS, are critical players in both CNS homeostasis and disease. We have previously demonstrated that microglia can be efficiently depleted by the administration of tamoxifen in Cx3cr1CreER/+Rosa26DTA/+ mice, with ensuing repopulation deriving from both the proliferation of residual CNS resident microglia and the engraftment of peripheral monocyte-derived microglia-like cells. In this study, tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ and Cx3cr1CreER/+ female and male mice. Experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, was induced by active immunization with myelin oligodendrocyte glycoprotein (MOG) one month after tamoxifen injections in Cx3cr1CreER/+Rosa26DTA/+ mice and Cx3cr1CreER/+ mice, a time point when the CNS niche was colonized by microglia derived from both CNS microglia and peripherally-derived macrophages. We demonstrate that engraftment of microglia-like cells following microglial depletion exacerbated EAE in Cx3cr1CreER/+Rosa26DTA/+ female mice as assessed by clinical symptoms and the expression of CNS inflammatory factors, but these findings were not evident in male mice. Higher major histocompatibility complex class II expression and cytokine production in the female CNS contributed to the sex-dependent EAE severity in mice following engraftment of microglia-like cells. An underestimated yet marked sex-dependent microglial activation pattern may exist in the injured CNS during EAE.

Download Full-text

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Journal of Endocrinology ◽

10.1677/joe.1.06063 ◽

2005 ◽

Vol 185 (2) ◽

pp. 243-252 ◽

Cited By ~ 72

Author(s):

M Merle Elloso ◽

Kristen Phiel ◽

Ruth A Henderson ◽

Heather A Harris ◽

Steven J Adelman

Keyword(s):

Multiple Sclerosis ◽

Estrogen Receptor ◽

Experimental Autoimmune Encephalomyelitis ◽

Immune Responses ◽

Clinical Symptoms ◽

Protective Effects ◽

Autoimmune Encephalomyelitis ◽

Selective Agonist ◽

Selective Ligands ◽

Experimental Autoimmune

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERα and ERβ. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17β-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERα-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERβ-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139–151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERβ agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERα-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

Download Full-text

Sex-Specific Effects of Microglia-Like Cell Engraftment During Experimental Autoimmune Encephalomyelitis

10.21203/rs.3.rs-26029/v1 ◽

2020 ◽

Author(s):

Jinming Han ◽

Keying Zhu ◽

Kai Zhou ◽

Ramil Hakim ◽

Sreenivasa Raghavan Sankavaram ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Immune Cell ◽

Clinical Symptoms ◽

Myeloid Cell ◽

Active Immunization ◽

Inflammatory Factors ◽

Male Mice ◽

Autoimmune Encephalomyelitis ◽

Peripheral Monocyte ◽

Experimental Autoimmune

Abstract BackgroundMultiple Sclerosis (MS) is a chronic neuroinflammatory disorder of the central nervous system (CNS) that usually presents in young adults and predominantly in females. Microglia, a major resident immune cell in the CNS, are critical players in both CNS homeostasis and disease. We have previously demonstrated that microglia can be efficiently depleted by the administration of tamoxifen in Cx3cr1CreER/+Rosa26DTA/+ mice, with ensuing repopulation deriving from both the proliferation of residual CNS resident microglia and the engraftment of peripheral monocyte-derived microglia-like cells. MethodsTamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ and Cx3cr1CreER/+ female and male mice. Experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, was induced by active immunization with myelin oligodendrocyte glycoprotein one month after tamoxifen injections in Cx3cr1CreER/+Rosa26DTA/+ mice and Cx3cr1CreER/+ mice, a time point when the CNS niche was colonized by microglia derived from both CNS microglia and peripherally-derived macrophages. CNS myeloid cell compositions during acute and chronic EAE were measured by flow cytometry.ResultsWe demonstrate that engraftment of microglia-like cells following microglial depletion exacerbated EAE in Cx3cr1CreER/+Rosa26DTA/+ female mice as assessed by clinical symptoms and the expression of CNS inflammatory factors, but these findings were not evident in male mice. Higher major histocompatibility complex class II expression and cytokine production in the female CNS contributed to the sex-dependent EAE severity in mice following engraftment of microglia-like cells. ConclusionThe engraftment of microglia-like cells following microglial depletion exacerbated EAE in females. An underestimated yet marked sex-dependent microglial activation pattern may exist in the injured CNS during EAE.

Download Full-text

Cannabidiol Regulates Gene Expression in Encephalitogenic T cells Using Histone Methylation and noncoding RNA during Experimental Autoimmune Encephalomyelitis

Scientific Reports ◽

10.1038/s41598-019-52362-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Xiaoming Yang ◽

Marpe Bam ◽

Prakash S. Nagarkatti ◽

Mitzi Nagarkatti

Keyword(s):

Gene Expression ◽

T Cells ◽

Transcription Factors ◽

Experimental Autoimmune Encephalomyelitis ◽

Histone Methylation ◽

Noncoding Rna ◽

Immune Modulation ◽

Clinical Symptoms ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

Abstract Cannabidiol (CBD) has been shown by our laboratory to attenuate experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In this study, we used microarray and next generation sequencing (NGS)-based approaches to determine whether CBD would alter genome-wide histone modification and gene expression in MOG sensitized lymphocytes. We compared H3K4me3 and H3K27me3 marks in CD4+ T cells from naïve, EAE and CBD treated EAE mice by ChIP-seq. Although the overall methylation level of these two histone marks did not change significantly, the signal intensity and coverage differed in individual genes, suggesting that CBD may modulate gene expression by altering histone methylation. Further analysis showed that these histone methylation signals were differentially enriched in the binding sites of certain transcription factors, such as ZNF143 and FoxA1, suggesting that these transcription factors may play important roles in CBD mediated immune modulation. Using microarray analysis, we found that the expression pattern of many EAE-induced genes was reversed by CBD treatment which was consistent with its effect on attenuating the clinical symptoms of EAE. A unique finding of this study was that the expression of many miRNAs and lncRNAs was dramatically affected by CBD. In summary, this study demonstrates that CBD suppresses inflammation through multiple mechanisms, from histone methylation to miRNA to lncRNA.

Download Full-text

Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing–Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice

Pharmaceutics ◽

10.3390/pharmaceutics13070925 ◽

2021 ◽

Vol 13 (7) ◽

pp. 925

Author(s):

Khalid Alhazzani ◽

Sheikh F. Ahmad ◽

Naif O. Al-Harbi ◽

Sabry M. Attia ◽

Saleh A. Bakheet ◽

...

Keyword(s):

T Cells ◽

Immune Cells ◽

Cd4 T Cells ◽

Inflammatory Markers ◽

Clinical Symptoms ◽

Autoimmune Encephalomyelitis ◽

Disease Symptoms ◽

Stat3 Signaling ◽

Relapsing Remitting ◽

Experimental Autoimmune

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that leads to demyelination and neuronal loss in the central nervous system. Immune cells of lymphoid and myeloid origin play a significant role in the initiation and amplification of neuronal inflammation in MS. STAT3 signaling plays a pivotal role in both myeloid and lymphoid immune cells, such as neutrophils and CD4+ T cells, through regulation of their inflammatory potential. Dysregulation in STAT3 signaling in myeloid and lymphoid cell compartments has been reported in MS. In this report, we attempted to investigate the effect of a small molecular inhibitor of STAT3, i.e., Stattic, in a relapsing–remitting (RR) model of experimental autoimmune encephalomyelitis (EAE). The effect of Stattic was investigated for clinical features, oxidative stress parameters, and Th17-related signaling in both the periphery and brain of SJL/J mice. Our data report that p-STAT3 expression is elevated in granulocytes, CD4+ T cells, and brain tissue in myelin proteolipid protein (PLP)-immunized SJL/J mice, which is associated with the presence of clinical symptoms and upregulation of inflammatory markers in these cells/tissues. Treatment with Stattic leads to the amelioration of disease symptoms and attenuation of inflammatory markers in neutrophils (iNOS/nitrotyrosine/IL-1β), CD4+ T cells (IL-17A/IL-23R), and brain tissue (IL-17A/iNOS/IL-1β/MPO activity/lipid peroxides) in mice with EAE. These data suggest that the blockade of STAT3 signaling in cells of lymphoid and myeloid origin may cause the attenuation of systemic and neuronal inflammation, which could be responsible for the amelioration of disease symptoms in an RR model of EAE. Therefore, pharmacological inhibition of STAT3 in RRMS could be a potential therapeutic strategy.

Download Full-text

IL-23p19 and CD5 antigen-like form a possible novel heterodimeric cytokine and contribute to experimental autoimmune encephalomyelitis development

Scientific Reports ◽

10.1038/s41598-021-84624-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hideaki Hasegawa ◽

Izuru Mizoguchi ◽

Naoko Orii ◽

Shinya Inoue ◽

Yasuhiro Katahira ◽

...

Keyword(s):

T Cells ◽

Experimental Autoimmune Encephalomyelitis ◽

Clinical Symptoms ◽

Critical Role ◽

Autoimmune Encephalomyelitis ◽

Gm Csf ◽

Reduced Frequency ◽

Macrophage Colony ◽

Deficient Mice ◽

Experimental Autoimmune

AbstractAmong various cytokines, interleukin (IL)-12 family cytokines have very unique characteristics in that they are composed of two distinct subunits and these subunits are shared with each other. IL-23, one of the IL-12 family cytokines, consists of p19 and p40 subunits, is mainly produced by antigen-presenting cells, and plays a critical role in the expansion and maintenance of pathogenic helper CD4+ T (Th)17 cells. Since we initially found that p19 is secreted in the culture supernatant of activated CD4+ T cells, we have further investigated the role of p19. p19 was revealed to associate with CD5 antigen-like (CD5L), which is a repressor of Th17 pathogenicity and is highly expressed in non-pathogenic Th17 cells, to form a composite p19/CD5L. This p19/CD5L was shown to activate STAT5 and enhance the differentiation into granulocyte macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells. Both CD4+ T cell-specific conditional p19-deficient mice and complete CD5L-deficient mice showed significantly alleviated experimental autoimmune encephalomyelitis (EAE) with reduced frequency of GM-CSF+CD4+ T cells. During the course of EAE, the serum level of p19/CD5L, but not CD5L, correlated highly with the clinical symptoms. Thus, the composite p19/CD5L is a possible novel heterodimeric cytokine that contributes to EAE development with GM-CSF up-regulation.

Download Full-text