The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 202, P. 106710 - 106710

Published: Oct. 28, 2024

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by damage to specific cell populations in the nervous system, ultimately leading disability or death. Effective treatments for these still lacking, due limited understanding their pathogeneses, which involve multiple cellular and molecular pathways. The triggering an immune response is feature neurodegenerative disorders. A critical challenge intricate interplay between neuroinflammation, neurodegeneration, responses, not yet fully characterized. In recent years, cyclic GMP-AMP synthase (cGAS)-stimulator interferon gene (STING) pathway, crucial intracellular DNA sensing, has gradually gained attention. However, roles this pathway within types such as cells, glial neuronal its contribution ND pathogenesis, remain elucidated. review, we systematically explore how cGAS-STING signaling links various with related effector pathways under context NDs multifaceted therapeutic directions. We emphasize discovery condition-dependent heterogeneity integral diverse responses potential targets. Additionally, review pathogenic role activation Parkinson's disease, ataxia-telangiectasia, amyotrophic lateral sclerosis. focus on complex bidirectional Alzheimer's Huntington's sclerosis, revealing double-edged nature disease progression. objective elucidate pivotal pathogenesis catalyze new insights facilitating development novel strategies.

Language: Английский

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Upregulated Expression of Macrophage Migration Inhibitory Factor, Its Analogue D-Dopachrome Tautomerase, and the CD44 Receptor in Peripheral CD4 T Cells from Clinically Isolated Syndrome Patients with Rapid Conversion to Clinical Defined Multiple Sclerosis

Medicina, Journal Year: 2019, Volume and Issue: 55(10), P. 667 - 667

Published: Oct. 1, 2019

Background and objectives: Macrophage Migration Inhibitory Factor (MIF) D-Dopachrome Tautomerase (DDT) are two pleiotropic primarily, but not exclusively, proinflammatory cytokines belonging to the MIF family of that have recently been shown be implicated in pathogenesis progressive forms human Multiple Sclerosis (MS) experimental model counterpart rodents. Materials Methods: We presently evaluated a transcriptomic analysis expression MIF, DDT, their receptors CD74 CD44, co-receptors CXCR2, CXCR4, CXCR7 peripheral blood patients with Clinically Isolated Syndrome (CIS), rapid progression clinical defined MS. Results: Our reveals CD44 overexpressed CD4+ T cells from CIS, as compared healthy controls. Accordingly, significant overlap was observed between genes CIS regulatory network. This upregulated appeared unique for cells, other immune including CD8+ B monocytes these exhibited levels molecules were superimposable those Conclusions: Overall, our data suggest overexpression cytokine signature may occur this phenomenon disease, offering possibility represent both diagnostic marker therapeutic target.

Language: Английский

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A focus on allogeneic mesenchymal stromal cells as a versatile therapeutic tool for treating multiple sclerosis

Stem Cell Research & Therapy, Journal Year: 2021, Volume and Issue: 12(1)

Published: July 13, 2021

Abstract Multiple sclerosis (MS) is a central nervous system (CNS) chronic illness with autoimmune, inflammatory, and neurodegenerative effects characterized by neurological disorder axonal loss signs due to myelin sheath autoimmune T cell attacks. Existing drugs, including disease-modifying drugs (DMD), help decrease the intensity frequency of MS attacks, inflammatory conditions, CNS protection from damage. As they cannot improve repair show side effects, new therapeutic options are required. In this regard, their neuroprotection properties, immunomodulatory ability differentiate into neurons, transplantation mesenchymal stromal cells (MSCs) can be used for therapy. The use adipose-derived MSCs (AdMSCs) or autologous bone marrow (BMSCs) has demonstrated unexpected invasive painful isolation method, inadequate amounts (BM) stem cells, anti-inflammatory impact reduction AdMSCs that isolated fat patients, number differentiation potential an increase in age BMSCs donor. Researchers have been trying search alternate tissue sources MSCs, especially fetal annexes, which could offer novel choice therapy limitation low yield collection methods MSCs. treatment discussed review. Finally, it suggested allogeneic appealing alternative hence solution

Language: Английский

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What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

Neurotherapeutics, Journal Year: 2022, Volume and Issue: 19(3), P. 785 - 807

Published: April 1, 2022

In the past two decades, monoclonal antibodies (mAbs) have revolutionized treatment of multiple sclerosis (MS). However, a remarkable number mAbs failed due to negative study results were withdrawn because unexpected serious adverse events (SAEs) or studies being halted for other reasons. While trials with positive outcomes are usually published in prestigious journals, merely as abstracts not at all. This review summarizes MS that either phase II–III trials, been interrupted various reasons, from market since 2015. The main conclusions can be drawn these 'negative' experiences follows. proven safe autoimmune conditions, will same safety profile immunopathogenetic differences diseases (e.g., daclizumab). Identification SAEs clinical is difficult highlighting importance IV studies. Memory B cells central players immunopathogenesis tabalumab). pathophysiological mechanisms disease progression independent leukocyte 'outside-in' traffic which drives relapses MS. Therefore, therapies progressive must able sufficiently cross blood–brain barrier. Sufficiently long trial duration and multicomponent outcome measures important success on remyelination-promoting mainly depends sufficient high dose mAb, optimal readout ‘proof concept’, time initiation, appropriate selection patients. Failed strategies highly better understand assumed immunopathophysiological optimizing future designs.

Language: Английский

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B-Cell-Directed Therapies: A New Era in Multiple Sclerosis Treatment

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, Journal Year: 2022, Volume and Issue: 50(3), P. 355 - 364

Published: May 16, 2022

ABSTRACT: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) that often progresses to severe disability. Previous studies have highlighted role T cells in pathophysiology; however, success B-cell-targeted therapies has led an increased interest how B contribute immunopathology. In this review, we summarize evidence B-cell involvement MS mechanisms, starting with pathology and moving on review aspects cell immunobiology potentially relevant MS. We describe current theories critical contributions inflammatory CNS milieu MS, namely (i) production autoantibodies, (ii) antigen presentation, (iii) proinflammatory cytokines (bystander activation), (iv) EBV involvement. second part medications targeted patients their position therapeutic armamentarium based clinical trials real-world data. Covered strategies include targeting surface molecules such as CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) CD19 (inebilizumab), necessary for activation activating factor (BAFF) (belimumab) Bruton’s Tyrosine Kinase (BTK) (evobrutinib). finally discuss use therapeutics pregnancy.

Language: Английский

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