cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 1, 2025

Impairment of the inner blood-retinal barrier (iBRB) leads to various blinding diseases including diabetic retinopathy (DR). The cGAS-STING pathway has emerged as a driving force cardiovascular destruction, but its impact on neurovascular system is unclear. Here, we show that cGAMP, endogenous STING agonist, causes iBRB breakdown and retinal degeneration thorough P2RX7-mediated transport into microglia. Extracellular cGAMP were determined in tissue samples from patients with proliferative DR (PDR) db/db mice. Histological, molecular, bioinformatic behavioral analysis accessed effects iBRB. Single-cell RNA sequencing identified primary cell type responsive cGAMP. Specific inhibitors P2RX7-deficienct mice used evaluate P2RX7' role transporter. therapeutic P2RX7 inhibitor tested was detected aqueous humor PDR elevated vitreous activation mouse retinas. administration led STING-dependent neuron degeneration. Microglia cells responding essential for cGAMP-induced visual impairment. ATP-gated transporter required import Contrary previous thought nonselectively transports only at extremely high ATP concentrations, human directly binds activates under physiological conditions. Clinically, microglial signature recapitulated fibrovascular membranes PDR, being predominantly expressed Inhibiting reduced cGAMP-STING activation, protected improved survival Our study reveals mechanism cGAMP-mediated suggests targeting microglia may mitigate deleterious linked

Language: Английский

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Beyond Diabetes: Semaglutide's Role in Modulating Mood Disorders through Neuroinflammation Pathways

Cellular and Molecular Neurobiology, Journal Year: 2025, Volume and Issue: 45(1)

Published: March 10, 2025

Language: Английский

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Galectin-3 shapes toxic alpha-synuclein strains in Parkinson’s disease

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 146(1), P. 51 - 75

Published: May 18, 2023

Abstract Parkinson’s Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) known to be main component LB. It has also been reported interact with several proteins organelles. Galectin-3 (GAL3) have detrimental function diseases. galactose-binding protein without catalytic activity expressed mainly activated microglial cells central nervous system (CNS). GAL3 previously found outer layer LB post-mortem brains. However, role PD yet elucidated. In samples, we identified an association between all subjects studied. was linked less αSYN other deposits, including pale bodies. associated disrupted lysosomes. vitro studies demonstrate that exogenous recombinant Gal3 internalised neuronal cell lines primary where it interacts endogenous αSyn fibrils. addition, aggregation experiments show affects spatial propagation stability pre-formed fibrils resulting short, amorphous toxic strains. To further investigate these observations vivo, take advantage WT Gal3KO mice subjected intranigral injection adenovirus overexpressing human as model. line our , under conditions, genetic deletion leads increased intracellular accumulation within remarkably preserved integrity motor function. Overall, data suggest prominent for process formation, leading production short species detriment larger strains which triggers mouse model PD.

Language: Английский

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CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 5, 2024

Abstract Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells CNS. Here we optimized a brain regimen that leads rapid, robust, persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This combines busulfan myeloablation six days Colony-stimulating factor 1 receptor inhibitor PLX3397. Single-cell analyses revealed unappreciated heterogeneity with most expressing genes characteristic homeostatic microglia, brain-border-associated macrophages, unique markers. Cytokine analysis CNS showed transient inductions myeloproliferative chemoattractant cytokines help repopulate niche. Bone marrow transplant progranulin-deficient mice conditioned PLX3397 restored progranulin eyes normalized lipofuscin storage, proteostasis, lipid metabolism. study advances our understanding repopulation by hematopoietic-derived demonstrates its potential for treating progranulin-dependent neurodegeneration.

Language: Английский

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Transcriptional and epigenetic regulation of microglia in maintenance of brain homeostasis and neurodegeneration

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Jan. 9, 2023

The emerging role of microglia in brain homeostasis, neurodegeneration, and neurodevelopmental disorders has attracted considerable interest. In addition, recent developments microglial functions associated pathways have shed new light on their fundamental the immunological surveillance brain. Understanding interconnections between microglia, neurons, non-neuronal cells opened up additional avenues for research this evolving field. Furthermore, study at transcriptional epigenetic levels enhanced our knowledge these native immune cells. Moreover, exploring various facets biology will facilitate early detection, treatment, management neurological disorders. Consequently, present review aimed to provide comprehensive insight its influence development, disease, highlights as potential therapeutic targets neurodegenerative diseases.

Language: Английский

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Microglial Caspase-3 is essential for modulating hippocampal neurogenesis

Brain Behavior and Immunity, Journal Year: 2023, Volume and Issue: 112, P. 206 - 219

Published: June 15, 2023

Adult hippocampal neurogenesis (AHN) is a process involved in numerous neurodegenerative diseases. Many researchers have described microglia as key component regulating the formation and migration of new neurons along rostral migratory stream. Caspase-3 cysteine-aspartate-protease classically considered one main effector caspases cell death program process. In addition to this classical function, we identified role protein modulator microglial function; however, its action on neurogenic processes unknown. The aim present study identify neurogenesis-related functions. To address study, conditional knockout mice line were used. Using tool, wanted elucidate function hippocampus, region which adult takes place. After reduction microglia, mutant showed especially dentate gyrus region, inherently associated neurogenesis. addition, found doublecortin-positive mice, corresponds neurons. Furthermore, using high-resolution image analysis, also observed phagocytic capacity lacking Caspase-3. Behavioral analysis object recognition Y-maze tests altered memory learning absence Finally, specific located specifically niche positive for Galectin 3 colocalized with Cleaved-Caspase-3 control mice. Taken together, these results essential highlight relevant phenotype maintenance AHN hippocampus.

Language: Английский

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Galectin-3 depletion tames pro-tumoural microglia and restrains cancer cells growth

Cancer Letters, Journal Year: 2024, Volume and Issue: 591, P. 216879 - 216879

Published: April 16, 2024

Galectin-3 (Gal-3) is a multifunctional protein that plays pivotal role in the initiation and progression of various central nervous system diseases, including cancer. Although involvement Gal-3 tumour progression, resistance to treatment immunosuppression has long been studied different cancer types, mainly outside system, its elevated expression myeloid glial cells underscores profound impact on brain's immune response. In this context, microglia infiltrating macrophages, predominant non-cancerous within microenvironment, play critical roles establishing an immunosuppressive milieu diverse brain tumours. Through utilisation primary cell cultures immortalised microglial lines, we have elucidated promoting migration, invasion, phenotypic activation. Furthermore, employing two distinct vivo models encompassing (glioblastoma) secondary tumours (breast metastasis), our histological transcriptomic analysis show depletion triggers robust pro-inflammatory response notably based interferon-related pathways. Interestingly, prominently observed tumour-associated macrophages (TAMs), resulting suppression growth.

Language: Английский

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BTK regulates microglial function and neuroinflammation in human stem cell models and mouse models of multiple sclerosis

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 22, 2024

Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation multiple sclerosis (MS) but not addressed therapeutically. Bruton's tyrosine kinase (BTK) is expressed both B-lymphocytes and innate immune cells, including microglia, where its role poorly understood. BTK inhibition may provide therapeutic benefit within CNS targeting adaptive immunity-mediated disease progression MS. Using CNS-penetrant inhibitor (BTKi), we demonstrate robust vivo effects mouse models of We further identify BTK-dependent transcriptional signature vitro, using BTKi tolebrutinib, human induced pluripotent stem cell (hiPSC)-derived complex hiPSC-derived tri-culture composed neurons, astrocytes, revealing modulation neuroinflammatory pathways relevant Finally, that MS tissue B-cells with increased levels lesions. Our data rationale for diminish neuroinflammation accumulation. cells remains Here, authors show modulates microglial report vitro animal

Language: Английский

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Plasma galectin-3 can be considered as a non-invasive marker to predict the prognosis of ACLF patients with new typing

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 31, 2025

Very recently, we creatively put forward a new classification for ACLF patients, which lays the foundation establishment of prognostic model that can accurately predict prognosis patients. Herein, found: galectin-3 levels were higher in type A patients compared to those B patients; expression was closely correlated with TBil, PTA/INR and MELD; is an independent predictive factor rapid progression ACLF, exhibited superior value than MELD score; survival rate remarkably lower expression. Collectively, be considered as non-invasive biomarker typing. Our findings help advance time window prediction from 4 weeks baseline, thereby identifying who really need liver transplantation earlier improving

Language: Английский

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Macrophages protect against sensory axon loss in peripheral neuropathy

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Language: Английский

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