Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: July 7, 2023

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune cytokine that belongs to the TNF superfamily of receptor ligands. The exists as either transmembrane or soluble molecule, and targets two distinct receptors, TNF-α 1 (TNFR1) 2 (TNFR2), which activate different signaling cascades downstream genes. cellular responses depend on its molecular form, targeted receptor, concentration levels. plays multifaceted role in normal physiology highly relevant human health disease. In central nervous system (CNS), this regulates homeostatic functions, such neurogenesis, myelination, blood-brain barrier permeability synaptic plasticity. However, it can also potentiate neuronal excitotoxicity CNS inflammation. pleiotropism various roles CNS, whether deleterious, only emphasizes functional complexity cytokine. Anti-TNF-α therapy has demonstrated effectiveness treating autoimmune inflammatory diseases emerged significant treatment option for diseases. Nevertheless, crucial recognize effects therapeutic target are diverse complex. Contrary initial expectations, anti-TNF-α been found have detrimental multiple sclerosis. This article focuses describing roles, both physiological pathological, CNS. Additionally, discusses specific disease processes dependent regulated by rationale use target.

Language: Английский

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Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Jan. 20, 2024

Abstract Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination nerves. Mitochondrial dysfunction has been implicated in pathogenesis MS, as studies have shown abnormalities mitochondrial activities, metabolism, DNA (mtDNA) levels, morphology immune individuals with MS. The presence dysfunctions contributes to immunological dysregulation neurodegeneration This review provided comprehensive overview associated focusing on potential consequences metabolic reprogramming function. Current challenges future directions field immune-metabolic MS its therapeutic target were also discussed.

Language: Английский

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Arachidonic acid-derived lipid mediators in multiple sclerosis pathogenesis: fueling or dampening disease progression?

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Jan. 17, 2024

Abstract Background Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration. Considering increasing prevalence among young adults worldwide disabling phenotype disease, deeper understanding complexity pathogenesis needed to ultimately improve diagnosis personalize treatment opportunities. Recent findings suggest that bioactive lipid mediators (LM) derived from ω-3/-6 polyunsaturated fatty acids (PUFA), also termed eicosanoids, may contribute MS pathogenesis. For example, disturbances in LM profiles especially those ω-6 PUFA arachidonic acid (AA) have been reported people with (PwMS), where they chronicity neuroinflammatory processes. Moreover, we previously shown certain AA-derived LMs associated neurodegenerative processes PwMS, suggesting are involved more pathological events than solely neuroinflammation. Yet, date, comprehensive overview contribution these MS-associated remains elusive. Main body This review summarizes critically evaluates current literature on eicosanoid biosynthetic pathway its key hallmarks during different stages. Various parts highlighted, namely, prostanoid, leukotriene, hydroxyeicosatetraenoic (HETEs) biochemical routes include specific enzymes cyclooxygenases (COXs) lipoxygenases (LOX) families. In addition, cellular sources their potential target cells based receptor expression will be discussed context MS. Finally, propose novel therapeutic approaches and/or modulation demyelination neurodegeneration Short conclusion The intrinsically linked aspects Therefore, intervention strategies, aim accurately modulating towards biosynthesis beneficial LMs, can potentially patient- subtype-specific opportunities combat Graphical

Language: Английский

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A New Strategy in Modulating the Protease-Activated Receptor 2 (Par2) in Autoimmune Diseases

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 410 - 410

Published: Jan. 6, 2025

Autoimmune diseases are complex conditions characterized by immune-mediated tissue damage and chronic inflammation. Protease-activated receptor 2 (Par2) has been implicated in these diseases, exhibiting dual roles that complicate its therapeutic potential. This review examines the perplexing functions of Par2, which promotes inflammation through immune cell activation while facilitating healing damaged organs. By analyzing findings across diverse autoimmune conditions, including rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, we highlight how context location Par2 determine effects. Recent studies from our laboratory have resolved some contradictions distinguishing Par2’s tissue-reparative functions. These insights pave way for context-specific strategies, such as selective modulators, can mitigate enhancing repair. However, achieving precision modulation remains a significant challenge, necessitating further research into signaling pathways. underscores complexity transformative potential disease management, offering nuanced perspective on duality implications.

Language: Английский

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Immune Regulatory Functions of Macrophages and Microglia in Central Nervous System Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5925 - 5925

Published: March 21, 2023

Macrophages can be characterized as a very multifunctional cell type with spectrum of phenotypes and functions being observed spatially temporally in various disease states. Ample studies have now demonstrated possible causal link between macrophage activation the development autoimmune disorders. How these cells may contributing to adaptive immune response potentially perpetuating progression neurodegenerative diseases neural injuries is not fully understood. Within this review, we hope illustrate role that macrophages microglia play initiators CNS by offering evidence of: (1) types responses processes antigen presentation each disease, (2) receptors involved macrophage/microglial phagocytosis disease-related debris or molecules, and, finally, (3) implications macrophages/microglia on pathogenesis diseases.

Language: Английский

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Chitinase-3-like 1-protein in CSF: a novel biomarker for progression in patients with multiple sclerosis

Neurological Sciences, Journal Year: 2023, Volume and Issue: 44(9), P. 3243 - 3252

Published: March 29, 2023

Abstract Background Chitinase -3-like 1-protein (CHI3L1) is a glycoside secreted by monocytes, microglia, and activated astrocytes. Its distribution in inflammatory lesions denotes its role astrocytic response to modulate CNS inflammation. In multiple sclerosis (MS), CHI3L1 levels have been found be influenced disease severity, activity, progression. We aimed measure CSF level of patients with MS correlate disability measures for possible as biomarker Methods Fifty-two (30 relapsing-remitting 22 progressive MS) thirty-five age sex-matched healthy controls were included. They all underwent full clinical assessment (including cognitive scales), radiological assessment, CHI3L1. Results Patients had higher than controls. forms relapsing forms. There positive correlations between duration, number attacks, total EDSS, who showed worse performance MMSE BICAMS more T2 MRI brain. A cut off value 154 ng/mL was RRMS PMS patients. Conclusion can considered increases RRMS. Also, high associated including motor, cognitive, aspects.

Language: Английский

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Immunomodulation in allergic rhinitis: Insights from Th2 cells and NLRP3/IL‐18 pathway

Cell Biochemistry and Function, Journal Year: 2024, Volume and Issue: 42(3)

Published: March 30, 2024

Abstract Allergic rhinitis (AR) is characterized by nasal symptoms such as rubbing and sneezing, often triggered allergen exposure. The purpose of this study to dissect the roles NLRP3‐mediated immune modulation macrophage pyroptosis in modulating T cell differentiation within context ovalbumin (OVA)‐induced AR mice. OVA‐induced was established mice, evaluating symptoms, infiltration, cytokine levels, differentiation. Manipulations using NLRP3−/−, ASC−/− clodronate liposome treatment, NLRP3 inhibitor MCC950 were performed assess their impact on responses. Following OVA stimulation, increased observed group along with augmented GATA3 expression elevated IL‐4 IL‐1b indicative Th2 polarization cellular involvement. NLRP3−/− mice exhibited reduced CD3+ cells post induction, implicating AR. Macrophage depletion led decreased IgE highlighting involvement allergic Further investigations revealed enhanced pyroptosis, influencing Th1/Th2 models. IL‐18 released through induced differentiation, distinct from IL‐1b. Additionally, effectively mitigated responses reducing infiltration. This comprehensive unravels pivotal role balance regulation Targeting pathways emerged a promising strategy alleviate providing insights for potential therapeutic interventions management.

Language: Английский

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Remodeling of T-cell mitochondrial metabolism to treat autoimmune diseases

Autoimmunity Reviews, Journal Year: 2024, Volume and Issue: 23(6), P. 103583 - 103583

Published: June 1, 2024

T cells are key drivers of the pathogenesis autoimmune diseases by producing cytokines, stimulating generation autoantibodies, and mediating tissue cell damage. Distinct mitochondrial metabolic pathways govern direction T-cell differentiation function rely on specific nutrients enzymes. Metabolic substrate uptake metabolism form foundational elements for activation, proliferation, differentiation, effector function, contributing to dynamic interplay between immunological signals in coordinating adaptive immunity. Perturbations availability enzyme activity may impair immunosuppressive fostering autoreactive responses disrupting immune homeostasis, ultimately disease pathogenesis. A growing body studies has explored how processes regulate diverse subsets such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), hepatitis (AIH), inflammatory bowel (IBD), psoriasis. This review describes coordination biology metabolism, including electron transport chain (ETC), oxidative phosphorylation, amino acid fatty one‑carbon metabolism. study elucidated intricate crosstalk programs, signal transduction pathways, transcription factors. summarizes potential therapeutic targets signaling diseases, providing insights future studies.

Language: Английский

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Astrogliosis in multiple sclerosis and neuro-inflammation: what role for the notch pathway?

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 23, 2023

Multiple sclerosis is an autoimmune inflammatory disease of the central nervous system leading to neurodegeneration. It affects 2.3 million people worldwide, generally younger than 50. There no known cure for disease, and current treatment options - mainly immunotherapies limit progression are few associated with serious side effects. In multiple sclerosis, disruption blood-brain barrier early event in pathogenesis lesions, predisposing edema, excito-toxicity infiltration into system. Recently, vision blood brain structure integrity has changed include contributions from all components neurovascular unit, among which astrocytes. During neuro-inflammation, astrocytes become reactive. They undergo morphological molecular changes named “astrogliosis” driving conversion acute injury a chronic neurodegenerative state. Astrogliosis mechanisms minimally explored despite their significance regulating response during sclerosis. Therefore, this review, we take stock state knowledge regarding astrogliosis neuro-inflammation highlight role NOTCH signaling process astrocyte reactivity. Indeed, very detailed nomenclature published nature neurosciences 2021, listing reactive markers fully identified literature, doesn’t cover signaling. Hence, discuss evidence supporting NOTCH1 receptor as regulator pathophysiology notably human experimental models.

Language: Английский

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Interferon-gamma ameliorates experimental autoimmune encephalomyelitis by inducing homeostatic adaptation of microglia

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 2, 2023

Compelling evidence has shown that interferon (IFN)-γ dual effects in multiple sclerosis and its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection EAE on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, impact at peak EAE, CNS infiltrating myeloid (MC) microglia (MG), underlying cellular molecular were investigated. administration resulted disease amelioration attenuation neuroinflammation associated significantly lower frequencies CD11b + less infiltration inflammatory demyelination. A significant reduction activated MG enhanced resting was determined by flow cytometry immunohistrochemistry. Primary MC/MG cultures obtained from spinal cord IFN-γ-treated mice ex vivo re-stimulated low dose (1 ng/ml) neuroantigen, promoted higher induction CD4 regulatory T (Treg) increased transforming growth factor (TGF)-β secretion. Additionally, primary produced nitrite response to LPS challenge control MC/MG. had frequency CX3CR1 high expressed levels program death ligand 1 (PD-L1) PBS-treated mice. Most PD-L1 Ly6G - markers (Tmem119, Sall2, P2ry12), indicating they represented enriched subset (CX3CR1 MG). Amelioration clinical symptoms dependent STAT-1. RNA-seq analyses revealed treatment homeostatic MG, upregulating expression genes tolerogenic anti-inflammatory roles down-regulating pro-inflammatory genes. These highlight master role plays regulating microglial activity provide new insights into involved therapeutic EAE.

Language: Английский

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