scholarly journals FGF/FGFR Pathways in Multiple Sclerosis and in Its Disease Models

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 884
Author(s):  
Ranjithkumar Rajendran ◽  
Gregor Böttiger ◽  
Christine Stadelmann ◽  
Srikanth Karnati ◽  
Martin Berghoff
Keyword(s):  
Multiple Sclerosis ◽  
Therapeutic Option ◽  
Fgf Signaling ◽  
Autoimmune Encephalomyelitis ◽  
Akt Phosphorylation ◽  
Fgf2 Expression ◽  
The Central Nervous System ◽  
Phase Ii And Iii ◽  
Specific Deletion ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)35–55-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS.

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

2021 ◽  
Author(s):  
William E. Barclay ◽  
M. Elizabeth Deerhake ◽  
Makoto Inoue ◽  
Toshiaki Nonaka ◽  
Kengo Nozaki ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Animal Model ◽  
Cell Death ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

ABSTRACTInflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.

scholarly journals TGF-β in Mice Ameliorates Experimental Autoimmune Encephalomyelitis in Regulating NK Cell Activity

2019 ◽  
Vol 28 (9-10) ◽  
pp. 1155-1160 ◽  
Author(s):  
J. Xu ◽  
Y. Wang ◽  
H. Jiang ◽  
M. Sun ◽  
J. Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Nk Cells ◽  
Nk Cell ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis is a disease characterized by inflammation and demyelination located in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model for multiple sclerosis (MS). Although the roles of T cells in MS/EAE have been well investigated, little is known about the functions of other immune cells in the neuroinflammation model. Here we found that an essential cytokine transforming growth factor β (TGF-β) which could mediate the differentiation of Th17/regulatory T cells was implicated in the natural killer (NK) cells’ activity in EAE. In EAE mice, TGF-β expression was first increased at the onset and then decreased at the peak, but the expressions of TGF-β receptors and downstream molecules were not affected in EAE. When we immunized the mice with MOG antigen, it was revealed that TGF-β treatment reduced susceptibility to EAE with a lower clinical score than the control mice without TGF-β. Consistently, inflammatory cytokine production was reduced in the TGF-β treated group, especially with downregulated pathogenic interleukin-17 in the central nervous system tissue. Furthermore, TGF-β could increase the transcription level of NK cell marker NCR1 both in the spleen and in the CNS without changing other T cell markers. Meanwhile TGF-β promoted the proliferation of NK cell proliferation. Taken together, our data demonstrated that TGF-β could confer protection against EAE model in mice through NK cells, which would be useful for the clinical therapy of MS.

scholarly journals Role of Immune Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

2020 ◽  
Author(s):  
Sarah Dhaiban ◽  
Mena Al-Ani ◽  
Noha Mousaad Elemam ◽  
Mahmood H Al-Aawad ◽  
Zeinab Al-Rawi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cells ◽  
T Regulatory Cells ◽  
Cell Types ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS) characterized by varying degrees of demyelination of uncertain etiology, and is associated with specific environmental and genetic factors. Upon recognition of CNS antigens, the immune cells initiate an inflammatory process which leads to destruction and deterioration of the neurons. Innate immune cells such as macrophages, dendritic cells and natural killer cells are known to play critical roles in the pathogenesis of MS. Also, the activation of peripheral CD4+ T cells by CNS antigens leads to their extravasation into the CNS causing damages that exacerbates the disease. This could be accompanied by dysregulation of T regulatory cells and other cell types functions. Experimental autoimmune encephalomyelitis (EAE) is a mouse model used to study the pathophysiology of MS disease. In this review, we highlight the roles of innate and adaptive immune players in the pathogenesis of MS and EAE.

scholarly journals The Benefits and Detriments of Macrophages/Microglia in Models of Multiple Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Khalil S. Rawji ◽  
V. Wee Yong
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Neurotrophic Factors ◽  
Neurological Diseases ◽  
Oligodendrocyte Precursor Cells ◽  
Activated Macrophages ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Experimental Autoimmune

The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia.

Identification of a Val I 45 IIe substitution in the human myelin oligodendrocyte glycoprotein: lack of association with multiple sclerosis

1997 ◽  
Vol 3 (6) ◽  
pp. 377-381 ◽  
Author(s):  
D. Rodriguez ◽  
B. Della Gaspera ◽  
B. Zalc ◽  
J-J. Hauw ◽  
B. Fontaine ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Demyelinating Diseases ◽  
Target Antigen ◽  
Restriction Enzyme Digestion ◽  
Autoimmune Encephalomyelitis ◽  
Potential Implication ◽  
The Central Nervous System ◽  
Major Target ◽  
Experimental Autoimmune

Myelin/oligodendrocyte glycoprotein (MOG) is a major target antigen in experimental autoimmune encephalomyelitis and it has been suggested that it may as well play a key role in the demyelination process in multiple sclerosis (MS). As MOG variants could be pathogenic in autoimmune demyelinating diseases of the central nervous system, we analysed the coding sequence of MOG in MS patients and described a G→A transition occurring in exon 3 of the human MOG gene. The mutation predicts that isoleucine substitutes for a valine at codon I 45 (Val 145 lle) in the transmembrane region of the protein. This is the first aminoacid substitution reported in human MOG. The polymorphism can be detected by restriction enzyme digestion of genomic DNA or reverse-transcribed PCR amplified products, making it a simple tool to detect a potential implication of MOG alleles in susceptibility to MS by association study. The analysis of 83 unrelated MS patients and 82 unrelated healthy controls showed that the polymorphism is found in similar proportions in MS patients (18%) and controls (14.6%). It is therefore unlikely that the MOG Val 145 lle variant is responsible for genetic susceptibility to MS.

The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes

2014 ◽  
Vol 0 (0) ◽  
Author(s):  
Maziar Gooshe ◽  
Amir Hossein Abdolghaffari ◽  
Maria Elsa Gambuzza ◽  
Nima Rezaei
Keyword(s):  
Multiple Sclerosis ◽  
Host Defense ◽  
Toll Like Receptors ◽  
Autoimmune Encephalomyelitis ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Ms Therapy ◽  
Experimental Autoimmune

AbstractThe interaction between the immune and nervous systems suggests invaluable mechanisms for several pathological conditions, especially neurodegenerative disorders. Multiple sclerosis (MS) is a potentially disabling chronic autoimmune disease, characterized by chronic inflammation and neurodegenerative pathology of the central nervous system. Toll-like receptors (TLRs) are an important family of receptors involved in host defense and in recognition of invading pathogens. The role of TLRs in the pathogenesis of autoimmune disorders such as MS is only starting to be uncovered. Recent studies suggest an ameliorative role of TLR3 and a detrimental role of other TLRs in the onset and progression of MS and experimental autoimmune encephalomyelitis, a murine model of MS. Thus, modulating TLRs can represent an innovative immunotherapeutic approach in MS therapy. This article outlines the role of these TLRs in MS, also discussing TLR-targeted agonist or antagonists that could be used in the different stages of the disease.

scholarly journals Role of Peripheral Immune Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Sci ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 12
Author(s):  
Sarah Dhaiban ◽  
Mena Al-Ani ◽  
Noha Mousaad Elemam ◽  
Mahmood H. Al-Aawad ◽  
Zeinab Al-Rawi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cells ◽  
Autoimmune Encephalomyelitis ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Exact Etiology ◽  
The Central Nervous System ◽  
Peripheral Immune Cells ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the myelination of the neurons present in the central nervous system (CNS). The exact etiology of MS development is unclear, but various environmental and genetic factors might play a role in initiating the disease. Experimental autoimmune encephalomyelitis (EAE) is a mouse model that is used to study the pathophysiology of MS disease as well as the effects of possible therapeutic agents. In addition, autoreactive immune cells trigger an inflammatory process upon the recognition of CNS antigens, which leads to destruction of the neurons. These include innate immune cells such as macrophages, dendritic cells, and natural killer cells. Additionally, the activation and extravasation of adaptive immune cells such as CD4+ T cells into the CNS may lead to further exacerbation of the disease. However, many studies revealed that immune cells could have either a protective or pathological role in MS. In this review, we highlight the roles of innate and adaptive immune cellular and soluble players that contribute to the pathogenesis of MS and EAE, which may be used as potential targets for therapy.

scholarly journals IFP35 family proteins promote neuroinflammation and multiple sclerosis

2021 ◽  
Vol 118 (32) ◽  
pp. e2102642118
Author(s):  
Xizhong Jing ◽  
Yongjie Yao ◽  
Danning Wu ◽  
Hao Hong ◽  
Xu Feng ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Immune Cells ◽  
Neutralizing Antibodies ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Multiple Cells ◽  
Excessive Activation ◽  
Experimental Autoimmune

Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B–dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi−/−, Ifp35−/−, or administration of neutralizing antibodies against IFP35 alleviated the immune cells’ infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.

scholarly journals Caspase-11 Mediates Oligodendrocyte Cell Death and Pathogenesis of Autoimmune-Mediated Demyelination

2001 ◽  
Vol 193 (1) ◽  
pp. 111-122 ◽  
Author(s):  
Shin Hisahara ◽  
Junying Yuan ◽  
Takashi Momoi ◽  
Hideyuki Okano ◽  
Masayuki Miura
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Central Nervous System ◽  
Cell Death ◽  
Caspase 3 ◽  
Inflammatory Diseases ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Deficient Mice ◽  
Experimental Autoimmune

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11–deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11–deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.

scholarly journals Regulation of Immune Cell Infiltration into the CNS by Regional Neural Inputs Explained by the Gate Theory

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yasunobu Arima ◽  
Daisuke Kamimura ◽  
Lavannya Sabharwal ◽  
Moe Yamada ◽  
Hidenori Bando ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Immune Cell Infiltration ◽  
Virus Infections ◽  
Autoimmune Encephalomyelitis ◽  
Mechanical Disruption ◽  
The Central Nervous System ◽  
Experimental Autoimmune

The central nervous system (CNS) is an immune-privileged environment protected by the blood-brain barrier (BBB), which consists of specific endothelial cells that are brought together by tight junctions and tight liner sheets formed by pericytes and astrocytic end-feet. Despite the BBB, various immune and tumor cells can infiltrate the CNS parenchyma, as seen in several autoimmune diseases like multiple sclerosis (MS), cancer metastasis, and virus infections. Aside from a mechanical disruption of the BBB like trauma, how and where these cells enter and accumulate in the CNS from the blood is a matter of debate. Recently, using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found a “gateway” at the fifth lumber cord where pathogenic autoreactive CD4+ T cells can cross the BBB. Interestingly, this gateway is regulated by regional neural stimulations that can be mechanistically explained by the gate theory. In this review, we also discuss this theory and its potential for treating human diseases.

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