Therapeutic Targeting of Immune Cell Autophagy in Multiple Sclerosis: Russian Roulette or Silver Bullet?

Autoimmune And Inflammatory Diseases ◽

The Central Nervous System

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding nerve fibers that project from neurons. The pathological hallmark of MS is multiple areas of myelin loss accompanied by inflammation within the CNS, resulting in loss of cognitive function that ultimately leads to paralysis. Recent studies in MS have focused on autophagy, a cellular self-eating process, as a potential target for MS treatment. Here, we review the contribution of immune cell autophagy to the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS. A better understanding of the role of autophagy in different immune cells to EAE might inform the development of novel therapeutic approaches in MS and other autoimmune and inflammatory diseases.

Impact of Exercise on Immunometabolism in Multiple Sclerosis

Journal of Clinical Medicine ◽

10.3390/jcm9093038 ◽

2020 ◽

Vol 9 (9) ◽

pp. 3038 ◽

Cited By ~ 1

Author(s):

Remsha Afzal ◽

Jennifer K Dowling ◽

Claire E McCoy

Keyword(s):

Multiple Sclerosis ◽

Cell Function ◽

Immune Cell ◽

Therapeutic Benefits ◽

Demyelinating Lesions ◽

Inflammatory State ◽

Autoimmune Condition ◽

Axonal Degradation

Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms’ mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

Role of Immune Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

10.20944/preprints202011.0477.v1 ◽

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 ◽

Chronic Autoimmune Disease ◽

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.

Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic Implications

Current Neuropharmacology ◽

10.2174/1570159x19666210629145351 ◽

2021 ◽

Vol 19 ◽

Author(s):

Xu Wang ◽

Zhen Liang ◽

Shengnan Wang ◽

Di Ma ◽

Mingqin Zhu ◽

...

Keyword(s):

Multiple Sclerosis ◽

Gut Microbiota ◽

Demyelinating Disease ◽

Inflammatory Diseases ◽

Intestinal Barrier ◽

Autoimmune Response ◽

Therapeutic Implications ◽

Underlying Mechanisms

: The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on the gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota has also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.

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

Reviews in the Neurosciences ◽

10.1515/revneuro-2014-0026 ◽

2014 ◽

Vol 0 (0) ◽

Cited By ~ 5

Author(s):

Maziar Gooshe ◽

Amir Hossein Abdolghaffari ◽

Maria Elsa Gambuzza ◽

Nima Rezaei

Keyword(s):

Multiple Sclerosis ◽

Host Defense ◽

Toll Like Receptors ◽

Pathological Conditions ◽

Chronic Autoimmune Disease ◽

Ms Therapy ◽

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.

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1609905114 ◽

2017 ◽

Vol 114 (7) ◽

pp. E1168-E1177 ◽

Cited By ~ 45

Author(s):

Justin E. Lengfeld ◽

Sarah E. Lutz ◽

Julian R. Smith ◽

Claudiu Diaconu ◽

Cameron Scott ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune Cell ◽

Disease Onset ◽

Cell Junctions ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

T Cell Infiltration ◽

Cell Adhesion Molecule 1

Disruption of the blood–brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4+ T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.

IL-17 controls central nervous system autoimmunity through the intestinal microbiome

Science Immunology ◽

10.1126/sciimmunol.aaz6563 ◽

2021 ◽

Vol 6 (56) ◽

pp. eaaz6563 ◽

Cited By ~ 2

Author(s):

Tommy Regen ◽

Sandrine Isaac ◽

Ana Amorim ◽

Nicolás Gonzalo Núñez ◽

Judith Hauptmann ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Inflammatory Diseases ◽

Intestinal Microbiome ◽

Interleukin 17A ◽

Effector Cytokines ◽

Interleukin-17A– (IL-17A) and IL-17F–producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type–like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F–deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.

Th17-Related Cytokines as Potential Discriminatory Markers between Neuromyelitis Optica (Devic’s Disease) and Multiple Sclerosis—A Review

International Journal of Molecular Sciences ◽

10.3390/ijms22168946 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8946

Author(s):

Karina Maciak ◽

Sylwia Pietrasik ◽

Angela Dziedzic ◽

Justyna Redlicka ◽

Joanna Saluk-Bijak ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune Response ◽

Neuromyelitis Optica ◽

Inflammatory Diseases ◽

Similar Treatment ◽

Devic’S Disease ◽

Devic's Disease ◽

Clinical Pictures

Multiple sclerosis (MS) and Devic’s disease (NMO; neuromyelitis optica) are autoimmune, inflammatory diseases of the central nervous system (CNS), the etiology of which remains unclear. It is a serious limitation in the treatment of these diseases. The resemblance of the clinical pictures of these two conditions generates a partial possibility of introducing similar treatment, but on the other hand, a high risk of misdiagnosis. Therefore, a better understanding and comparative characterization of the immunopathogenic mechanisms of each of these diseases are essential to improve their discriminatory diagnosis and more effective treatment. In this review, special attention is given to Th17 cells and Th17-related cytokines in the context of their potential usefulness as discriminatory markers for MS and NMO. The discussed results emphasize the role of Th17 immune response in both MS and NMO pathogenesis, which, however, cannot be considered without taking into account the broader perspective of immune response mechanisms.

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

Journal of Experimental Medicine ◽

10.1084/jem.193.1.111 ◽

2001 ◽

Vol 193 (1) ◽

pp. 111-122 ◽

Cited By ~ 87

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 ◽

Deficient Mice ◽

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.

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

Mediators of Inflammation ◽

10.1155/2013/898165 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 16

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 ◽

Mechanical Disruption ◽

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.