NF-κB inhibitor suppresses experimental autoimmune neuritis in mice via declining macrophages polarization to M1 type

Guillain–Barre’ syndrome (GBS) is an acute inflammatory and immune-mediated demyelinating disease of peripheral nervous system (PNS). Macrophages playing a central role in its animal model, experimental autoimmune neuritis (EAN) has been well-accepted. Additionally, NF-κB inhibitors has been used to treat cancers and showed beneficial effects. Here we investigated the therapeutic effect of M2 macrophage and NF-κB pathway is correlated with macrophages activation in experimental autoimmune neuritis (EAN) in C57BL/6 mice. We demonstrated that M2 macrophage transfusion can alleviate the clinical symptoms of EAN by reducing the proportion of M1 macrophage in the peak period, inhibiting the phosphorylation of NF-κB p65. The NF-κB inhibitor (BAY-11-7082) could alleviate the clinical symptoms of EAN and shorten the duration of symptoms by reducing the proportion of M1 macrophages and the expression of pro-inflammatory cytokines. Consequently, BAY-11-7082 exhibits strong potential as a therapeutic strategy for ameliorating EAN by influencing the balance of M1/M2 macrophages and inflammatory cytokines.

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Celastrol ameliorates experimental autoimmune neuritis by shifting the polarization of M1/M2 macrophages via the hypoxic response pathway

10.21203/rs.3.rs-25002/v1 ◽

2020 ◽

Author(s):

Yun Qian ◽

Bo Tang ◽

Minhai Jiang ◽

Shan Lu ◽

Huan Huang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Macrophage Polarization ◽

Polarization State ◽

Immunofluorescence Staining ◽

Experimental Autoimmune Neuritis ◽

Inflammatory Infiltration ◽

Histological Changes ◽

Hypoxic Response ◽

Effective Therapeutic Strategy ◽

Experimental Autoimmune

Abstract BackgroundGBS is an autoimmune disease characterized by inflammatory infiltration and demyelination of peripheral nerves. Macrophage polarization is involved in different stages of GBS. Altering the polarization of macrophages may be an effective therapeutic strategy for GBS. Celastrol was previously shown to contribute to anti-neuroinflammation. However, the mechanism underlying the effect of celastrol in GBS animal model experimental autoimmune neuritis (EAN) is unclear. We hypothesized that celastrol may shift the polarization of macrophages through the NRF /HIF-1αpathway.MethodsClinical scores, weight and histological changes were assessed to investigate the effects of celastrol on EAN. To detect the polarization state of macrophages, flow cytometry and immunofluorescence staining were applied. Inflammation cytokines were evaluated by ELISA. The expression of NRF2 and HIF-1α were detected by western-blot and immunofluorescence staining.ResultsCelastrol treatment significantly ameliorates the severity and neuroinflammation of EAN. The polarization state of macrophages from M1 to M2 was observed upon celastrol application. Consistently, pro-inflammatory cytokines were decreased, whereas anti-inflammatory cytokines were increased upon celastrol treatment. Furthermore, we found that celastrol treatment may increase expression of Nrf2 and decrease the expression of HIF-1α. ConclusionTaken together, these data demonstrate that celastrol may ameliorate the severity and neuroinflammation of EAN via promoting the polarization state of macrophages into M2, likely by modulating the hypoxic response. Celastrol may therefore serve as a novel therapeutic agent for GBS.

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Cerebrospinal Fluid (CSF) Exchange with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Experimental Autoimmune Encephalomyelitis

International Journal of Molecular Sciences ◽

10.3390/ijms20071793 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1793 ◽

Cited By ~ 3

Author(s):

Michael Valitsky ◽

Sandrine Benhamron ◽

Keren Nitzan ◽

Dimitrios Karussis ◽

Ezra Ella ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Experimental Autoimmune Encephalomyelitis ◽

Clinical Symptoms ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Neuronal Cell ◽

Human Mesenchymal Stem Cells ◽

Autoimmune Encephalomyelitis ◽

Beneficial Effects ◽

Experimental Autoimmune

The complexity of central nervous system (CNS) degenerative/inflammatory diseases and the lack of substantially effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. We suggest a novel approach directed for the elimination of pathogenic agents from the CNS and, in parallel, its enrichment with an array of neuroprotective substances, using a “cerebrospinal fluid (CSF) exchange” procedure, in which endogenous (pathogenic) CSF is removed and replaced by artificial CSF (aCSF) enriched with secretions of human mesenchymal stem cells (MSCs). MSCs produce a variety of neuroprotective agents and have shown beneficial effects when cells are transplanted in animals and patients with CNS diseases. Our data show that MSCs grown in aCSF secrete neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant agents; moreover, MSC-secretions-enriched-aCSF exerts neuroprotective and immunomodulatory effects in neuronal cell lines and spleen lymphocytes. Treatment of experimental-autoimmune-encephalomyelitis (EAE) mice with this enriched-aCSF using an intracerebroventricular (ICV) CSF exchange procedure (“CSF exchange therapy”) caused a significant delay in the onset of EAE and amelioration of the clinical symptoms, paralleled by a reduction in axonal damage and demyelination. These findings point to the therapeutic potential of the CSF exchange therapy using MSC-secretions-enriched-aCSF in inflammatory/degenerative diseases of the CNS.

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IL-18 deficiency inhibits both Th1 and Th2 cytokine production but not the clinical symptoms in experimental autoimmune neuritis

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2006.12.001 ◽

2007 ◽

Vol 183 (1-2) ◽

pp. 162-167 ◽

Cited By ~ 4

Author(s):

Rui-Sheng Duan ◽

Xing-Mei Zhang ◽

Eilhard Mix ◽

Hernan Concha Quezada ◽

Abdu Adem ◽

...

Keyword(s):

Cytokine Production ◽

Clinical Symptoms ◽

Experimental Autoimmune Neuritis ◽

Th2 Cytokine ◽

Th1 And Th2 ◽

Experimental Autoimmune

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IL-12 p40 monomer is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress EAE

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2000653117 ◽

2020 ◽

Vol 117 (35) ◽

pp. 21557-21567

Author(s):

Susanta Mondal ◽

Madhuchhanda Kundu ◽

Malabendu Jana ◽

Avik Roy ◽

Suresh B. Rangasamy ◽

...

Keyword(s):

Demyelinating Disease ◽

Clinical Symptoms ◽

Inhibitory Effect ◽

The Other ◽

Healthy Controls ◽

Specific Monoclonal Antibody ◽

Collagen Induced Arthritis ◽

Autoimmune Encephalomyelitis ◽

The Central Nervous System ◽

Experimental Autoimmune

Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system. The IL-12 family of cytokines has four members, which are IL-12 (p40:p35), IL-23 (p40:p19), the p40 monomer (p40), and the p40 homodimer (p402). Since all four members contain p40 in different forms, it is important to use a specific monoclonal antibody (mAb) to characterize these molecules. Here, by using such mAbs, we describe selective loss of p40 in serum of MS patients as compared to healthy controls. Similarly, we also observed decrease in p40 and increase in IL-12, IL-23, and p402in serum of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as compared to control mice. Interestingly, weekly supplementation of mouse and human recombinant p40 ameliorated clinical symptoms and disease progression of EAE. On the other hand, IL-12, IL-23, and p402did not exhibit such inhibitory effect. In addition to EAE, p40 also suppressed collagen-induced arthritis in mice. Using IL-12Rβ1−/−, IL-12Rβ2−/−, and IL-12Rβ1+/−/IL-12Rβ2−/−mice, we observed that p40 required IL-12Rβ1, but not IL-12Rβ2, to suppress EAE. Interestingly, p40 arrested IL-12–, IL-23–, or p402-mediated internalization of IL-12Rβ1, but neither IL-12Rβ2 nor IL-23R, protected regulatory T cells, and suppressed Th1 and Th17 biasness. These studies identify p40 as an anti-autoimmune cytokine with a biological role different from IL-12, IL-23, and p402in which it attenuates autoimmune signaling via suppression of IL-12Rβ1 internalization, which may be beneficial in patients with MS and other autoimmune disorders.

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Effect of 1.25(OH)2D3 on experimental autoimmune neuritis and its mechanism

Trends in Immunotherapy ◽

10.24294/ti.v5.i2.1.1375 ◽

2021 ◽

Vol 5 (2.1) ◽

pp. 42

Author(s):

Di Nian ◽

Zhuohan Li ◽

Junjie Sun ◽

Peng Shi

Keyword(s):

Inflammatory Cytokines ◽

Body Weight Loss ◽

Clinical Score ◽

Therapeutic Effects ◽

Experimental Autoimmune Neuritis ◽

Transmission Electron ◽

New Strategy ◽

Ifn Γ ◽

Sciatic Nerves ◽

Experimental Autoimmune

Objective: To study the potential therapeutic effects of active vitamin D3 (1.25(OH)2D3) in the experimental autoimmune neuritis (EAN). Methods: The EAN model was established by actively immunizing Lewis rats with synthetic P0180–199 pepide and Freund’s complete adjuvant. 1.25(OH)2D3 treatment was given, weight change of rats and clinical score were analyzed. HE staining was used to detect the inflammatory cell infiltration of sciatic nerves and demyelination of sciatic nerves was observed by transmission electron microscope (TEM) at the same time. The expressions of inflammatory cytokines IL-17, IL-10, TGF-β, IFN-γ were detected by ELISA, and the expressions of Th17, Treg were examined by RT-PCR. Results: 1.25(OH)2D3 ameliorated body weight loss and myelin lesions. It decreased expressions of inflammatory cytokines IL-17, IFN-γ and RORrt while those of IL-10, TGF-β and FoxP3 were increased. Conclusions: 1.25(OH)2D3 can improve the clinical pathological changes of EAN rats, and the mechanism may be related to the changes of inflammatory cytokines. 1.25(OH)2D3 is expected to become a new strategy for the clinical treatment of GBS/EAN.

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Recombinant Trichinella spiralis 53-kDa protein activates M2 macrophages and attenuates the LPS-induced damage of endotoxemia

Innate Immunity ◽

10.1177/1753425916651984 ◽

2016 ◽

Vol 22 (6) ◽

pp. 419-432 ◽

Cited By ~ 7

Author(s):

Zhi-bin Chen ◽

Hao Tang ◽

Yan-bing Liang ◽

Wen Yang ◽

Jing-guo Wu ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Trichinella Spiralis ◽

Organ Damage ◽

Secretory Protein ◽

M2 Macrophage ◽

M2 Macrophages ◽

Microbial Infection ◽

M1 Macrophage ◽

Lethal Sepsis ◽

Anti Inflammatory

Sepsis is a serious clinical condition of excessive systemic immune response to microbial infection. The pro-inflammatory stage of sepsis is generally launched by innate cells such as macrophages. They release inflammatory cytokines, activate other immune cells and cause severe tissue/organ damage. In this study, we have revealed that recombinant Trichinella spiralis (TS) excretory–secretory protein (rTsP53) exhibited anti-inflammatory properties and rescued mice from LPS-induced endotoxemia, which is a common model for sepsis study, potentially through the induction of M2 macrophages. rTsP53 treatment significantly decreased inflammatory cytokines (IL-6, IFN-γ and TNF-α) and increased IL-4, IL-10, IL-13 and TGF-β secretion, both in circulation and in tissues. rTsP53 also induced the activation and infiltration of F4/80+CD163+ macrophages to inflammatory tissues, increased M2 macrophage-related Arg1 and Fizz1 expression, and decreased M1 macrophage-related iNOS expression. PCR array showed that rTsP53 activated several genes that involve the survival of macrophages and also anti-inflammatory genes such as SOCS3. Together, our results show that rTsP53 activates M2 macrophages, which has strong anti-inflammatory potential to prevent LPS-induced lethal sepsis.

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HIMF deletion ameliorates acute myocardial ischemic injury by promoting macrophage transformation to reparative subtype

Basic Research in Cardiology ◽

10.1007/s00395-021-00867-7 ◽

2021 ◽

Vol 116 (1) ◽

Author(s):

Yanjiao Li ◽

Min Dong ◽

Qing Wang ◽

Santosh Kumar ◽

Rui Zhang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Myocardial Infarct ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Myocardial Infarct Size ◽

Myocardial Repair ◽

Stat3 Signaling ◽

Gene Ablation ◽

M1 Macrophage ◽

Pro Inflammatory Cytokines

AbstractAppropriately manipulating macrophage M1/M2 phenotypic transition is a promising therapeutic strategy for tissue repair after myocardial infarction (MI). Here we showed that gene ablation of hypoxia-induced mitogenic factor (HIMF) in mice (Himf−/− and HIMFflox/flox;Lyz2-Cre) attenuated M1 macrophage-dominated inflammatory response and promoted M2 macrophage accumulation in infarcted hearts. This in turn reduced myocardial infarct size and improved cardiac function after MI. Correspondingly, expression of HIMF in macrophages induced expression of pro-inflammatory cytokines; the culturing medium of HIMF-overexpressing macrophages impaired the cardiac fibroblast viability and function. Furthermore, macrophage HIMF was found to up-regulate C/EBP-homologous protein (CHOP) expression, which exaggerated the release of pro-inflammatory cytokines via activating signal transducer of activator of transcription 1 (STAT1) and 3 (STAT3) signaling. Together these data suggested that HIMF promotes M1-type and prohibits M2-type macrophage polarization by activating the CHOP–STAT1/STAT3 signaling pathway to negatively regulate myocardial repair. HIMF might thus constitute a novel target to treat MI.

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Therapeutic Potential of Pien Tze Huang on Experimental Autoimmune Encephalomyelitis Rat

Journal of Immunology Research ◽

10.1155/2018/2952471 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Xuemei Qiu ◽

Hui Luo ◽

Xue Liu ◽

Qingqing Guo ◽

Kang Zheng ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Demyelinating Disease ◽

Clinical Symptoms ◽

Therapeutic Potential ◽

Clinical Severity ◽

Therapeutic Effects ◽

Autoimmune Encephalomyelitis ◽

Cytokines And Chemokines ◽

Pien Tze Huang ◽

Experimental Autoimmune

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). There is still lack of commercially viable treatment currently. Pien Tze Huang (PZH), a traditional Chinese medicine, has been proved to have anti-inflammatory, neuroprotective, and immunoregulatory effects. This study investigated the possible therapeutic effects of PZH on experimental autoimmune encephalomyelitis (EAE) rats, a classic animal model of MS. Male Lewis rats were immunized with myelin basic protein (MBP) peptide to establish an EAE model and then treated with three doses of PZH. Clinical symptoms, organ coefficient, histopathological features, levels of proinflammatory cytokines, and chemokines as well as MBP and Olig2 were analyzed. The results indicated that PZH ameliorated the clinical severity of EAE rats. It also remarkably reduced inflammatory cell infiltration in the CNS of EAE rats. Furthermore, the levels of IL-17A, IL-23, CCL3, and CCL5 in serum and the CNS were significantly decreased; the p-P65 and p-STAT3 levels were also downregulated in the CNS, while MBP and Olig2 in the CNS of EAE rats had a distinct improvement after PZH treatment. In addition, PZH has no obvious toxicity at the concentration of 0.486 g/kg/d. This study demonstrated that PZH could be used to treat MS.

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MicroRNA-155 inhibitor ameliorates collagen-induced arthritis by modulating the phenotype of pro-inflammatory macrophages in a mouse model

STEMedicine ◽

10.37175/stemedicine.v2i8.105 ◽

2021 ◽

Vol 2 (8) ◽

pp. e105

Author(s):

Yuanliang Chen ◽

Hong Sung Min ◽

Yongbai Wan ◽

Chaolai Jiang ◽

Xiaowei Yu

Keyword(s):

Mouse Model ◽

Inflammatory Cytokines ◽

In Vivo Studies ◽

Enzyme Linked Immunosorbent Assay ◽

M2 Macrophage ◽

M2 Macrophages ◽

Collagen Induced Arthritis ◽

M1 Macrophages ◽

M1 Macrophage

Background: The present study aims to investigate the roles of microRNA-155 in collagen-induced arthritis (CIA) and its underlying mechanisms. Methods: CIA mouse model was established and miR155 inhibitor was intravenously injected. In in vitro studies, bone marrow-derived macrophages (BMDMs) were induced into M1 macrophages followed by the treatment of miR155 inhibitor. Quantitative reverse transcription PCR (RT-qPCR) was applied to determine the mRNA expressions. Flow cytometry was applied to determine the frequency of M1 or M2 macrophages. Western blotting was determined to detect protein expressions. Enzyme-linked immunosorbent assay (ELISA) was applied to determine the levels of inflammatory cytokines and anti-collagen antibody. Results: The levels of miR155 were increased in macrophages from rheumatoid arthritis (RA) patients and M1 macrophages. The treatment of miR155 inhibitor decreased inflammatory cytokines in M1 macrophages. Besides, treatment of miR155 inhibitors promoted the differentiation of M0 macrophages into M2 macrophages. In vivo studies demonstrated that the treatment of miR155 inhibitors ameliorated the RA symptoms by decreasing inflammatory cytokines in the CIA mouse model. Treatment of miR155 also resulted in a decrease of M1 macrophage biomarker and an increase of M2 macrophage biomarker. Conclusion: microRNA-155 inhibitor ameliorates RA symptoms in part by regulating macrophage phenotypes.

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