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

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.

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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.

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

The American Journal of Chinese Medicine ◽

10.1142/s0192415x16500610 ◽

2016 ◽

Vol 44 (06) ◽

pp. 1099-1110 ◽

Cited By ~ 11

Author(s):

So Jin Bing ◽

Danbee Ha ◽

Insun Hwang ◽

Eunjin Park ◽

Ginnae Ahn ◽

...

Keyword(s):

T Cells ◽

Experimental Autoimmune Encephalomyelitis ◽

Panax Ginseng ◽

Clinical Symptoms ◽

Inflammatory Factors ◽

Protective Effects ◽

Autoimmune Encephalomyelitis ◽

Acidic Polysaccharide ◽

Relapsing Remitting ◽

Experimental Autoimmune

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.

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