Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease DOI Creative Commons
Sonia George, Nolwen L. Rey,

Trevor Tyson

и другие.

Molecular Neurodegeneration, Год журнала: 2019, Номер 14(1)

Опубликована: Авг. 16, 2019

Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute the pathogenesis Parkinson's disease (PD) and underlie spread α-syn neuropathology. Increased pro-inflammatory cytokine levels activated microglia are present in PD can promote aggregation. However, it unclear how influence cell-to-cell transfer. We developed a clinically relevant mouse model monitor prion-like between cells; we transplanted wild-type embryonic midbrain neurons into striatum overexpressing human (huα-syn) following adeno-associated viral injection substantia nigra. In this system, depleted or microglial cells determined effects on transfer huα-syn from host nigrostriatal implanted dopaminergic neurons, using presence within grafted as readout. First, compared mice with normal number which had pharmacologically ablated 80% striatum. With fewer microglia, observed increased accumulation neurons. Second, assessed context by one two stimuli, lipopolysaccharide (LPS) interleukin-4 (IL-4). LPS exposure led strong activation (as morphology, production an upregulation genes involved inflammatory response LPS-injected RNA sequencing analysis). significantly higher amounts contrast, IL-4 did not change proportion dopamine that contained relative controls. As expected, analysis striatal tissue revealed differential gene expression IL-4-injected mice; upregulated injected including several those response. The absence hyperstimulation affected brain. Our results suggest under resting, non-inflammatory conditions, modulate α-syn. Pharmacological regulation neuroinflammation could represent future avenue for limiting

Язык: Английский

Microglia Biology: One Century of Evolving Concepts DOI Creative Commons
Marco Prinz, Steffen Jung, Josef Priller

и другие.

Cell, Год журнала: 2019, Номер 179(2), С. 292 - 311

Опубликована: Окт. 1, 2019

Язык: Английский

Процитировано

1065
Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors DOI Creative Commons
Yang Yang, Huanan Wang,

Mohammed Kouadir

и другие.

Cell Death and Disease, Год журнала: 2019, Номер 10(2)

Опубликована: Фев. 12, 2019

Abstract The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release proinflammatory cytokines IL-1β IL-18. has been implicated in wide range diseases, including Alzheimer’s disease, Prion type 2 diabetes, some infectious diseases. It found variety stimuli danger-associated molecular patterns (DAMPs, such as silica uric acid crystals) pathogen-associated (PAMPs) can activate inflammasome, but specific regulatory mechanisms activation remain unclear. Understanding will enable development its inhibitors to treat NLRP3-related In this review, we summarize current understanding well specifically directly target NLRP3.

Язык: Английский

Процитировано

1053
Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications DOI Creative Commons

Marta Pajares,

Ana I. Rojo, Gina Manda

и другие.

Cells, Год журнала: 2020, Номер 9(7), С. 1687 - 1687

Опубликована: Июль 14, 2020

Parkinson’s disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from substantia nigra pars compacta. Although molecular bases for PD development are still little defined, extensive evidence human samples and animal models support involvement inflammation in onset or progression. However, exact trigger this response remains unclear. Here, we provide systematic review cellular mediators, i.e., microglia, astroglia endothelial cells. We also discuss genetic transcriptional control immunomodulatory role dopamine reactive oxygen species. Finally, summarize preclinical clinical approaches targeting neuroinflammation PD.

Язык: Английский

Процитировано

561
Pharmacological Inhibitors of the NLRP3 Inflammasome DOI Creative Commons
Ayesha Zahid, Bofeng Li, Arnaud John Kombe Kombe

и другие.

Frontiers in Immunology, Год журнала: 2019, Номер 10

Опубликована: Окт. 25, 2019

Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with plethora of pathogenic products and cellular associated stress damage. By far, the best studied most characterized inflammasome is NLRP3 inflammasome, consists (nucleotide-binding domain leucine-rich repeat (NLR) pyrin containing receptor 3), ASC (apoptosis-associated speck-like protein caspase recruitment domain), procaspase-1. Activation mediated highly diverse stimuli. Upon activation, recruits adapter protein, procaspase-1 resulting its cleavage inducing maturation, secretion inflammatory cytokines pyroptosis. However, aberrant activation implicated various diseases including diabetes, atherosclerosis, metabolic syndrome, cardiovascular, neurodegenerative diseases; raising tremendous clinical interest exploring potential inhibitors inflammasome. Recent investigations have disclosed pathway were validated through

Язык: Английский

Процитировано

558
Role of neuroinflammation in neurodegeneration development DOI Creative Commons
Weifeng Zhang, Dan Xiao, Qinwen Mao

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июль 12, 2023

Abstract Studies in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Amyotrophic lateral sclerosis, Huntington’s so on, have suggested that inflammation is not only a result of neurodegeneration but also crucial player this process. Protein aggregates which are very common pathological phenomenon can induce neuroinflammation further aggravates protein aggregation neurodegeneration. Actually, even happens earlier than aggregation. Neuroinflammation induced by genetic variations CNS cells or peripheral immune may deposition some susceptible population. Numerous signaling pathways range been to be involved the pathogenesis neurodegeneration, although they still far from being completely understood. Due limited success traditional treatment methods, blocking enhancing inflammatory considered promising strategies for therapy many them got exciting results animal models clinical trials. Some them, few, approved FDA usage. Here we comprehensively review factors affecting major pathogenicity sclerosis. We summarize current strategies, both clinic, diseases.

Язык: Английский

Процитировано

545
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets DOI Creative Commons
Chao Gao, Jingwen Jiang, Yuyan Tan

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 22, 2023

Abstract Microglia activation is observed in various neurodegenerative diseases. Recent advances single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified specific states correlate pathological hallmarks are associated functions. both exert protective function by phagocytosing clearing protein aggregates play detrimental roles due to excessive uptake of aggregates, which would lead microglial phagocytic ability impairment, neuroinflammation, eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes into a pro-inflammatory phenotype accelerates disease progression. also act as mobile vehicle propagate aggregates. Extracellular vesicles released from autophagy impairment all contribute progression Thus, enhancing phagocytosis, reducing microglial-mediated inhibiting exosome synthesis secretion, promoting conversion considered be promising strategies for the therapy Here we comprehensively review biology diseases, including Alzheimer’s disease, Parkinson’s multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia Lewy bodies Huntington’s disease. We summarize possible microglia-targeted interventions treatments against diseases preclinical clinical evidence cell experiments, animal studies, trials.

Язык: Английский

Процитировано

426
NLRP3 and pyroptosis blockers for treating inflammatory diseases DOI Creative Commons
Rebecca C. Coll, Kate Schroder, Pablo Pelegrı́n

и другие.

Trends in Pharmacological Sciences, Год журнала: 2022, Номер 43(8), С. 653 - 668

Опубликована: Май 3, 2022

The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key mediator of pathological inflammation in many diseases is an exciting drug target. Here, we review the molecular basis NLRP3 inhibition by drug-like small molecules under development novel therapeutics. We also summarize recent strategies to block pyroptosis approach suppress chronic inflammation. Major developments this area include elucidation mechanisms action (MoAs) which assembly gasdermin D (GSDMD)-induced pyroptosis. discuss status clinical trials using agents that specific components pathway, including their potential applications for treatment diseases.

Язык: Английский

Процитировано

422
Targeting the NLRP3 Inflammasome in Severe COVID-19 DOI Creative Commons
Tracey Freeman, Talia H. Swartz

Frontiers in Immunology, Год журнала: 2020, Номер 11

Опубликована: Июнь 23, 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within family Coronaviridae. It an enveloped single-stranded positive-sense RNA virus. Since December 2019, global expansion infection has occurred with widespread dissemination disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe complications occurs in 15% cases. Respiratory failure that can be accompanied by systemic inflammatory reaction characterized cytokine release. In cases, fatality caused rapid development lung injury characteristic distress (ARDS). Although ARDS complication SARS-CoV-2 infection, it not viral replication or causes tissue injury; rather, result dysregulated hyperinflammation response to infection. This pathology intense, stimulation innate immune triggers activation Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release its products including proinflammatory cytokines IL-6 IL-1β. Here we review literature describes pathogenesis NLRP3 describe important role targeting this for treatment COVID-19.

Язык: Английский

Процитировано

389
Parkinson disease and the immune system — associations, mechanisms and therapeutics DOI
Eng‐King Tan, Yinxia Chao, Andrew B. West

и другие.

Nature Reviews Neurology, Год журнала: 2020, Номер 16(6), С. 303 - 318

Опубликована: Апрель 24, 2020

Язык: Английский

Процитировано

363
Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy DOI Creative Commons
Luca Muzio, Alice Viotti, Gianvito Martino

и другие.

Frontiers in Neuroscience, Год журнала: 2021, Номер 15

Опубликована: Сен. 24, 2021

Microglia are the resident macrophages of central nervous system (CNS) acting as first line defense in brain by phagocytosing harmful pathogens and cellular debris. emerge from early erythromyeloid progenitors yolk sac enter developing before establishment a fully mature blood–brain barrier. In physiological conditions, during development, microglia contribute to CNS homeostasis supporting cell proliferation neural precursors. post-natal life, such cells preserving integrity neuronal circuits sculpting synapses. After injury, change their morphology down-regulate those genes homeostatic functions. However, it is still unclear whether changes accompanied molecular functional modifications that might pathological process. While comprehensive transcriptome analyses at single-cell level have identified specific gene perturbations occurring “pathological” microglia, precise protective/detrimental role neurological disorders far being elucidated. this review, results so obtained regarding neurodegenerative will be discussed. There solid sound evidence suggesting regulating functions disease pathology represent strategy develop future therapies aimed counteracting degeneration multiple sclerosis, Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis.

Язык: Английский

Процитировано

356