European Journal of Nuclear Medicine and Molecular Imaging, Год журнала: 2021, Номер 49(1), С. 174 - 185
Опубликована: Март 15, 2021
Язык: Английский
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
480
Frontiers in Immunology, Год журнала: 2021, Номер 12
Опубликована: Сен. 16, 2021
Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with central pathologies patients animal models. Recent single-cell sequencing transcriptomics indicate dynamic disease-associated microglia astrocyte profiles disease. Mitochondrial 18-kDa translocator protein is most widely investigated target for imaging. New generation tracers improved performance been developed evaluated along tau amyloid assessing progression continuum. Given that not exclusively expressed glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 purinergic P2X7 P2Y12 fractalkine triggering receptor on myeloid cells 2, advanced glycation end products. Promising should demonstrate a higher specificity cellular locations exclusive expression or activation status (pro- anti-inflammatory) highly specific ligand to enable vivo brain In this review, we summarised recent advances development outlook promising future.
Язык: Английский
Процитировано
119
Nature Communications, Год журнала: 2023, Номер 14(1)
Опубликована: Авг. 28, 2023
Abstract Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases activated microglia mouse brain disease models does not change a non-human primate model or common human describe genetic divergence the gene promoter, consistent with hypothesis increase myeloid cells depends on transcription factor AP1 unique to subset of rodent species within Muroidea superfamily. Finally, we identify LCP2 TFEC as potential markers microglial humans. These data emphasise related different phenomena than mice, TSPO-PET signals humans reflect density inflammatory rather state.
Язык: Английский
Процитировано
94
Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(3), С. e008054 - e008054
Опубликована: Март 1, 2024
Background The effectiveness of immune checkpoint inhibitors in colorectal cancer (CRC) is limited due to the low tumor neoantigen load and infiltration most microsatellite-stable (MSS) tumors. This study aimed develop a mitochondria-targeted photodynamic therapy (PDT) approach provoke host antitumor immunity MSS-CRC elucidate underlying molecular mechanisms. Methods role mechanism PDT inhibiting CRC progression inducing pyroptosis were evaluated both vitro vivo. effects sensitization on PD-1 blockade also assessed CT26 4T1 tumor-bearing mouse models. Results Here, we report that using IR700DX-6T, photosensitizer targeting mitochondrial translocation protein, may trigger an response initiated by CRC. Mechanistically, IR700DX-6T-PDT produced reactive oxygen species light irradiation promoted downstream p38 phosphorylation active caspase3 (CASP3)-mediated cleavage gasdermin E (GSDME), subsequently pyroptosis. Furthermore, enhanced sensitivity cells blockade. Decitabine, demethylation drug used treat hematologic neoplasms, disrupted abnormal methylation pattern GSDME cells, efficacy IR700DX-6T-PDT, elicited potent combination with IR700DX-6T-PDT. Conclusion Our work provides clear understanding immunogenic cell death triggered PDT, offering new for enhancing
Язык: Английский
Процитировано
23
Journal of Neuroinflammation, Год журнала: 2022, Номер 19(1)
Опубликована: Май 23, 2022
Abstract Background Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, executive functioning after being discharged from the hospital. We hypothesize sepsis disrupts microbiota–gut–brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction survivors. Methods To test our hypothesis, adult Wistar rats were subjected to cecal–ligation perforation (CLP) or sham (non-CLP) surgeries. The animals [ 11 C]PBR28 positron emission tomography (PET)/computed (CT) imaging at 24 h 10 days CLP non-CLP At surgery, we evaluated gut microbiome, bacterial metabolites, cytokines, microglia, astrocyte markers. Ten induction, novel object recognition (NOR) Morris water maze (MWM) assess their learning memory. Results Compared control group, 24-h 10-day groups showed increased uptake, glial cells count, cytokine levels brain. show modulates villus length crypt depth, alpha beta microbial diversities, fecal short-chain fatty acids (SCFAs). In addition, surviving significant decline compared group. Conclusions Since several pharmacological studies have failed prevent impairment survivors, better understanding of function microbiota provide new avenues for treating patients.
Язык: Английский
Процитировано
62
Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)
Опубликована: Март 18, 2022
Abstract Neuroinflammation is an important hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). An inflammatory reaction to neuronal injury deemed vital for health homeostasis. However, a continued activation the response can be detrimental remaining neurons aggravate disease process. Apart from modifying role, some evidence suggests that neuroinflammation may also contribute upstream cause disease. In this review, we will first focus on role in pathogenesis chromosome 9 open reading frame 72 gene ( C9orf72 ) hexanucleotide repeat expansions (HRE)-mediated ALS/FTD (C9-ALS/FTD). Additionally, discuss ex vivo studies finally, briefly summarize trials progress anti-inflammatory therapies.
Язык: Английский
Процитировано
47
European Journal of Neuroscience, Год журнала: 2022, Номер 55(5), С. 1322 - 1343
Опубликована: Янв. 27, 2022
Neuroinflammation is a significant contributor to Alzheimer's disease (AD). Until now, PET imaging of the translocator protein (TSPO) has been widely used depict neuroimmune endophenotype AD. The aim this review was provide an update results from 2018 and advance characterization biological basis TSPO in AD by re-examining function expression methodological aspects interest. Although signal obviously related microglia astrocytes AD, observed process remains uncertain might not be directly neuroinflammation. Further studies are required re-examine cellular significance underlying variation
Язык: Английский
Процитировано
41
Neurobiology of Disease, Год журнала: 2023, Номер 185, С. 106249 - 106249
Опубликована: Авг. 1, 2023
Epilepsy is one of most common chronic neurological disorders, and the antiseizure medications developed by targeting neurocentric mechanisms have not effectively reduced proportion patients with drug-resistant epilepsy. Further exploration cellular or molecular mechanism epilepsy expected to provide new options for treatment. Recently, more researches focus on brain network components other than neurons, among which microglia attracted much attention their diverse biological functions. As resident immune cells central nervous system, highly plastic transcription, morphology functional characteristics, can change dynamically in a context-dependent manner during progression In pathogenesis epilepsy, reactive interact epileptogenic performing crucial functions such as secretion soluble factors phagocytosis, thus continuously reshaping landscape epileptic microenvironment. Indeed, appear be both pro-epileptic anti-epileptic under different spatiotemporal contexts disease, rendering interventions biologically complex challenging. This comprehensive review critically summarizes pathophysiological role homeostasis alterations explores potential therapeutic modulatory targets microglia.
Язык: Английский
Процитировано
39
Brain Behavior and Immunity, Год журнала: 2023, Номер 113, С. 415 - 431
Опубликована: Авг. 3, 2023
The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity TSPO to identify brain processes appears vary greatly across disorders, disease stages, applied quantification methods. To advance potential biomarker evaluate inflammation anti-inflammatory therapies, better understanding its applicability disorders needed. We conducted transdiagnostic systematic review meta-analysis all vivo human case-control studies CNS. Specifically, we investigated direction, strength, heterogeneity associated with signal pre-specified regions, explored demographic methodological sources heterogeneity.We searched English peer-reviewed articles that differences. extracted details, outcomes, technical variables procedure. A random-effects was estimate standardized mean differences (SMD) lobar/whole-brain cortical grey matter (cGM), thalamus, cortico-limbic circuitry between different illness categories. Heterogeneity evaluated I2 statistic using subgroup meta-regression analyses radioligand generation, method, age, sex, publication year. Significance set at False Discovery Rate (FDR)-corrected P < 0.05.156 individual were included review, incorporating data 2381 healthy controls 2626 patients. 139 documented meta-analysable grouped into 11 Across categories, observed significantly higher cases compared cGM (n = 121 studies, SMD 0.358, PFDR 0.001, 68%), significant difference categories (P 0.004). increases only Alzheimer's (SMD 0.693, 64%) other neurodegenerative 0.929, 73%). Cortico-limbic 97 0.541, 67%) most prominent disease, mild cognitive impairment, mood multiple sclerosis. Thalamic involvement 79 0.393, 71%) sclerosis, chronic pain functional (all 0.05). Main outcomes systemic immunological viral infections, substance use schizophrenia traumatic injury not significant. identified between-study variance including strong effect method (explaining 25% variance; VT-based 0.000 versus reference tissue-based 0.630; F 20.49, df 1;103, 0.001), patient age (9% variance), generation (5% variance).This study first overarching findings humans several regions. robust specific types which widespread or focal depending on category. also found large horizontal (positive) shift estimates studies. Our results can support future optimize experimental design power calculations, by taking account type disorder, region-of-interest, radioligand, method.
Язык: Английский
Процитировано
27
The Journal of Headache and Pain, Год журнала: 2025, Номер 26(1)
Опубликована: Янв. 27, 2025
Neuropathic pain poses a significant clinical challenge, largely due to the incomplete understanding of its molecular mechanisms, particularly role mitochondrial dysfunction. Bioinformatics analysis revealed that pyroptosis and inflammatory responses induced by spared nerve injury (SNI) in spinal dorsal horn play critical initiation persistence neuropathic pain. Among factors involved, TSPO (translocator protein) emerged as key regulator. Our experimental findings showed expression was upregulated during pain, accompanied dysfunction, specifically manifested impaired biogenesis, disrupted dynamics (including insufficient biogenesis fusion-related proteins, well significantly increased fission-related proteins), activation pyroptosis. Pharmacological upregulation TSPO, but not downregulation, effectively alleviated SNI-induced hypersensitivity, improving function reducing Immunofluorescence staining confirmed primarily localized astrocytes, mirrored protective effects on health prevention. PCR array suggested strong association between regulation pathway AMPK-PGC-1α. Notably, inhibition AMPK-PGC-1α abolished balance suppression. Furthermore, Mendelian randomization GWAS data indicated linked relief. Through drug screening, docking, behavioral assays, we identified zopiclone promising TSPO-targeting for treatment. In summary, this study enhances our interplay health, highlighting potential therapeutic target management.
Язык: Английский
Процитировано
2