Microglial Transcriptional Signatures in the Central Nervous System: Toward A Future of Unraveling Their Function in Health and Disease DOI Creative Commons
Haley A. Vecchiarelli, Marie‐Ève Tremblay

Annual Review of Genetics, Journal Year: 2023, Volume and Issue: 57(1), P. 65 - 86

Published: June 29, 2023

Microglia, the resident immune cells of central nervous system (CNS), are primarily derived from embryonic yolk sac and make their way to CNS during early development. They play key physiological immunological roles across life span, throughout health, injury, disease. Recent transcriptomic studies have identified gene transcript signatures expressed by microglia that may provide foundation for unprecedented insights into functions. Microglial expression can help distinguish them macrophage cell types a reasonable degree certainty, depending on context. patterns further suggest heterogeneous population comprised many states vary according spatiotemporal diversity is most pronounced development, when extensive remodeling takes place, following disease or injury. A next step importance field will be identify functional performed these various microglial states, with perspective targeting therapeutically.

Language: Английский

Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting DOI Creative Commons
Marc Charabati, Michael A. Wheeler, Howard L. Weiner

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(7), P. 1309 - 1327

Published: March 1, 2023

Language: Английский

Citations

120
Microglia regulation of central nervous system myelin health and regeneration DOI
Sarah Kent, Véronique E. Miron

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 24(1), P. 49 - 63

Published: July 14, 2023

Language: Английский

Citations

66
Roles and regulation of microglia activity in multiple sclerosis: insights from animal models DOI
Félix Distéfano‐Gagné, Sara Bitarafan, Steve Lacroix

et al.

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(7), P. 397 - 415

Published: June 2, 2023

Language: Английский

Citations

56
Single cell approaches define neural stem cell niches and identify microglial ligands that can enhance precursor-mediated oligodendrogenesis DOI Creative Commons
Ashleigh Willis, Danielle Jeong, Yunlong Liu

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115194 - 115194

Published: Jan. 1, 2025

Language: Английский

Citations

2
Positron Emission Tomography with [18F]‐DPA‐714 Unveils a Smoldering Component in Most Multiple Sclerosis Lesions which Drives Disease Progression DOI Creative Commons
Mariem Hamzaoui, J. Garcia, Giacomo Boffa

et al.

Annals of Neurology, Journal Year: 2023, Volume and Issue: 94(2), P. 366 - 383

Published: April 11, 2023

To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18 kDa-translocator-protein-positron emission tomography (PET) -based classification each lesion according to innate immune cell content and localization. We assessed respective predictive phenotype diffuse inflammation on atrophy disability progression over 2 years.Thirty-six people with MS (disease duration 9 ± 6 years; 12 relapsing-remitting, 13 secondary-progressive, 11 primary-progressive) 19 healthy controls (HCs) underwent dynamic [18 F]-DPA-714-PET. At baseline after years, patients also magnetic resonance imaging (MRI) neurological examination. Based threshold significant defined by comparison F]-DPA-714 binding between HCs, white matter lesions were classified as homogeneously active (active center), rim-active (inactive center periphery), or nonactive. Longitudinal cortical was measured using Jacobian integration.Patients had higher normal-appearing (NAWM) cortex than HCs (respective standardized effect size = 1.15, 0.89, p 0.003 < 0.001). Out 1,335 non-gadolinium-enhancing 53% homogeneously-active (median 17 per patient MS), 6% 1 41% non-active 14 MS). The number homogenously-active strongest predictor longitudinal changes, associating (β 0.49, 0.023) Expanded Disability Status Scale (EDSS) changes 0.35, years. NAWM not associated volumetric clinical changes.The F]-DPA-714-PET revealed that an unexpectedly high proportion have smoldering component, which predicts progression. This suggests following acute phase, most develop chronic inflammatory promoting neurodegeneration ANN NEUROL 2023;94:366-383.

Language: Английский

Citations

41
Cross-talk between B cells, microglia and macrophages, and implications to central nervous system compartmentalized inflammation and progressive multiple sclerosis DOI Creative Commons
Hanane Touil, Rui Li, Leah Zuroff

et al.

EBioMedicine, Journal Year: 2023, Volume and Issue: 96, P. 104789 - 104789

Published: Sept. 11, 2023

B cells can be enriched within meningeal immune-cell aggregates of multiple sclerosis (MS) patients, adjacent to subpial cortical demyelinating lesions now recognized as important contributors progressive disease. This demyelination is notable for a 'surface-in' gradient neuronal loss and microglial activation, potentially reflecting the effects soluble factors secreted into CSF. We previously demonstrated that MS B-cell products are toxic oligodendrocytes neurons. The potential B-cell-myeloid cell interactions propagate considerable interest.Secreted MS-implicated pro-inflammatory effector or IL-10-expressing with regulatory were applied human brain-derived microglia monocyte-derived macrophages, subsequent assessment myeloid phenotype function through measurement their expression pro-inflammatory, anti-inflammatory homeostatic/quiescent molecules, phagocytosis (using flow cytometry, ELISA fluorescently-labeled myelin). Effects differentially activated on survival activation further studied.Secreted (but not IL-10 expressing cells) substantially induce cytokine (IL-12, IL-6, TNFα) by both macrophage (in GM-CSF dependent manner), while down-regulating quiescence-associated suppressing myelin phagocytosis. In contrast, upregulate molecules enhance Secreted from activation.Potential cross-talk between disease-relevant subsets resident CNS infiltrating macrophages may CNS-compartmentalized inflammation injury associated disease progression. These interaction represents an attractive therapeutic target agents such Bruton's tyrosine kinase inhibitors (BTKi) modulate responses cells.Stated in Acknowledgments section manuscript.

Language: Английский

Citations

29
Advances in research on immunocyte iron metabolism, ferroptosis, and their regulatory roles in autoimmune and autoinflammatory diseases DOI Creative Commons

Liuting Zeng,

Kailin Yang,

Ganpeng Yu

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(7)

Published: July 4, 2024

Abstract Autoimmune diseases commonly affect various systems, but their etiology and pathogenesis remain unclear. Currently, increasing research has highlighted the role of ferroptosis in immune regulation, with cells being a crucial component body’s system. This review provides an overview discusses relationship between ferroptosis, programmed cell death cells, autoimmune diseases. Additionally, it summarizes key targets such as GPX4 TFR, responses. Furthermore, release multiple molecules, including damage-associated molecular patterns (DAMPs), following by is examined, these molecules further influence differentiation function thereby affecting occurrence progression Moreover, secrete factors or metabolites, which also impact target organs tissues involved Iron chelators, chloroquine its derivatives, antioxidants, calreticulin have been demonstrated to be effective animal studies for certain diseases, exerting anti-inflammatory immunomodulatory effects. Finally, brief summary future perspectives on are provided, aiming guide disease treatment strategies.

Language: Английский

Citations

9
The protein kinase C modulator bryostatin-1 therapeutically targets microglia to attenuate neuroinflammation and promote remyelination DOI
Payam Gharibani, Efrat Abramson, Shruthi Shanmukha

et al.

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(780)

Published: Jan. 8, 2025

In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining balance among demyelination, neurodegeneration, myelin repair. Phagocytic regenerative functions of these CNS innate immune cells support remyelination, whereas chronic maladaptive inflammatory activation promotes lesion expansion disability, particularly progressive forms MS. No currently approved drugs convincingly target CNS, contributing to lack therapies aimed at promoting remyelination slowing disease progression for individuals with Here, we found that protein kinase C (PKC)–modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound established human safety profile, shifts transcriptional programs CNS-associated from proinflammatory phenotype vitro vivo. Treatment bryo-1 stimulated scavenger pathways, phagocytosis, secretion factors prevented neuroinflammatory reactive astrocytes while also neuroaxonal health oligodendrocyte differentiation. line findings, systemic treatment mice augmented after focal demyelinating injury. Our results demonstrate potential possibly wider class PKC modulators as myelin-regenerative supportive agents MS other neurologic diseases.

Language: Английский

Citations

1
Towards a biological view of multiple sclerosis from early subtle to clinical progression: an expert opinion DOI Creative Commons
Massimo Filippi, Maria Pia Amato, Carlo Avolio

et al.

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(2)

Published: Feb. 1, 2025

Language: Английский

Citations

1
Cellular rejuvenation protects neurons from inflammation-mediated cell death DOI Creative Commons
Sienna Drake, Abdulshakour Mohammadnia, Aliyah Zaman

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(2), P. 115298 - 115298

Published: Feb. 1, 2025

Highlights•RGCs demonstrate similar gene expression changes during EAE and aging•RGCs exhibit DNA damage, chromatin mark changes, nuclear lamina dystrophy in EAE•Patients with MS damage senescence-associated neurons•AAV2-OSK limits RGC death preserves visual acuity EAESummaryIn multiple sclerosis (MS), inflammation of the central nervous system results demyelination, neuroaxonal injury, cell death. However, molecular signals responsible for injury neurons are not fully characterized. Here, we profile transcriptome retinal ganglion cells (RGCs) experimental autoimmune encephalomyelitis (EAE) mice. Pathway analysis identifies a transcriptional signature reminiscent aged RGCs some senescent features, comparable present from patients MS. This is supported by immunostaining demonstrating alterations to envelope, modifications marks, accumulation damage. Transduction an Oct4-Sox2-Klf4 adeno-associated virus (AAV) rejuvenate enhances survival improves acuity. Collectively, these data reveal aging-like phenotype under pathological neuroinflammation support possibility that rejuvenation therapies or senotherapeutic agents could offer direct avenue neuroprotection neuroimmune disorders.Graphical abstract

Language: Английский

Citations

1