Single-cell RNA sequencing highlights the role of distinct natural killer subsets in amyotrophic lateral sclerosis DOI Creative Commons

Esther Álvarez‐Sánchez,

Álvaro Carbayo,

Natalia Valle‐Tamayo

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Abstract Background Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation the infiltration of immune cells into brain contribute to this process. However, no study has investigated peripheral blood ALS pathophysiology using single-cell RNA sequencing (scRNAseq). Methods We aimed characterize from identify ALS-related alterations at resolution. For purpose, mononuclear (PBMC) were isolated 14 patients cognitively unimpaired healthy individuals (HC), matched by age gender, cryopreserved until library preparation scRNAseq. analyzed differences proportions PBMC, gene expression, cell-cell communication patterns with compared HC, their association plasma neurofilament light (NfL) concentrations, surrogate biomarker for neurodegeneration. Flow cytometry was used validate cell type proportions. Results identified expansion CD56dim natural killer (NK) (fold change = 2; adj. p-value 0.0051), which mainly driven NK_2 subpopulation 3.12; 0.0001), mature cytotoxic NK subset. Our results revealed extensive expression cells, pointing towards activation response (adj. 9.2x10− 11) regulation lymphocyte proliferation 6.46x10− 6). changes other such as classical monocytes, distinct CD8 + effector memory T suggested enhanced antigen presentation via histocompatibility class-II 1.23x10− 8) ALS. The inference demonstrated interaction between HLA-E CD94:NKG2C different lymphocytes is unique blood. Finally, regression analysis proportion CD56bright along ALSFRS, disease duration, explained up 76.4% variance NfL levels. Conclusion reveal signature relevant occurring underscore proportion, signaling terminally differentiated (NK_2), well direct

Language: Английский

Regulatory T Cell- and Natural Killer Cell-Mediated Inflammation, Cerebral Vasospasm, and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage—A Systematic Review and Meta-Analysis Approach DOI Open Access

Andreas Pfnür,

Benjamin Mayer,

Lena Dörfer

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1276 - 1276

Published: Feb. 1, 2025

Aneurysmal subarachnoid hemorrhage (SAH) involves a significant influx of blood into the cerebrospinal fluid, representing severe form stroke. Despite advancements in aneurysm closure and neuro-intensive care, outcomes remain impaired due to cerebral vasospasm delayed ischemia (DCI). Previous pharmacological therapies have not successfully reduced DCI while improving overall outcomes. As result, efforts are underway better understand cellular molecular mechanisms involved. This review focuses on activation effects immune cells after SAH their interactions with neurotoxic vasoactive substances as well inflammatory mediators. Particular attention is given clinical studies highlighting roles natural killer (NK) regulatory T (Treg) cells. Alongside microglia, astrocytes, oligodendrocytes, NK Treg key contributors cascade following SAH. Their involvement modulating neuro-inflammatory response, vasospasm, underscores potential therapeutic targets prognostic markers post-SAH recovery process. We conducted systematic cell- cell-mediated inflammation ischemia. meta-analysis evaluate mortality focused mechanisms.

Language: Английский

Citations

2
Immune responses to central nervous system directed adeno-associated virus gene therapy: Does direct CNS delivery make a difference? DOI Creative Commons

Ashley L. Harkins,

Prajakta P Ambegaokar,

Allison M. Keeler

et al.

Neurotherapeutics, Journal Year: 2024, Volume and Issue: 21(4), P. e00435 - e00435

Published: July 1, 2024

Language: Английский

Citations

6
Single-cell RNA sequencing highlights the role of distinct natural killer subsets in sporadic amyotrophic lateral sclerosis DOI Creative Commons

Esther Álvarez‐Sánchez,

Álvaro Carbayo,

Natalia Valle‐Tamayo

et al.

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

Published: Jan. 23, 2025

Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation the infiltration of immune cells into brain contribute to this process. However, no study has investigated peripheral blood ALS pathophysiology using single-cell RNA sequencing (scRNAseq). We aimed characterize from identify ALS-related alterations at resolution. For purpose, mononuclear (PBMC) were isolated 14 patients cognitively unimpaired healthy individuals (HC), matched by age gender, cryopreserved until library preparation scRNAseq. analyzed differences proportions PBMC, gene expression, cell-cell communication patterns between HC, as well their association with plasma neurofilament light (NfL) concentrations, surrogate biomarker for neurodegeneration. Flow cytometry was used validate cell type proportions. identified expansion CD56dim natural killer (NK) (fold change = 2; adj. p-value 0.0051), mainly driven specific subpopulation, NK_2 3.12; 0.0001), which represent mature cytotoxic NK subset. Our results revealed extensive expression cells, pointing towards activation response (adj. 9.2 × 10− 11) regulation lymphocyte proliferation 6.46 6). also changes other such classical monocytes, distinct CD8 + effector memory T suggested enhanced antigen presentation via histocompatibility class-II 1.23 8) ALS. The inference demonstrated interaction HLA-E CD94:NKG2C different lymphocytes is unique compared HC. Finally, regression analysis proportion CD56bright along ALSFRS-r, disease duration, explained up 76.4% variance NfL levels. reveal signature relevant occurring underscore proportion, signaling terminally differentiated subpopulation (NK_2), possible

Language: Английский

Citations

0
The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases DOI Creative Commons
Yuxin Zhang, Meijuan Zou, Hao Wu

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 202, P. 106710 - 106710

Published: Oct. 28, 2024

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by damage to specific cell populations in the nervous system, ultimately leading disability or death. Effective treatments for these still lacking, due limited understanding their pathogeneses, which involve multiple cellular and molecular pathways. The triggering an immune response is feature neurodegenerative disorders. A critical challenge intricate interplay between neuroinflammation, neurodegeneration, responses, not yet fully characterized. In recent years, cyclic GMP-AMP synthase (cGAS)-stimulator interferon gene (STING) pathway, crucial intracellular DNA sensing, has gradually gained attention. However, roles this pathway within types such as cells, glial neuronal its contribution ND pathogenesis, remain elucidated. review, we systematically explore how cGAS-STING signaling links various with related effector pathways under context NDs multifaceted therapeutic directions. We emphasize discovery condition-dependent heterogeneity integral diverse responses potential targets. Additionally, review pathogenic role activation Parkinson's disease, ataxia-telangiectasia, amyotrophic lateral sclerosis. focus on complex bidirectional Alzheimer's Huntington's sclerosis, revealing double-edged nature disease progression. objective elucidate pivotal pathogenesis catalyze new insights facilitating development novel strategies.

Language: Английский

Citations

3
25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation DOI Creative Commons
Johnathan Romero, Danira Toral-Ríos, Jinsheng Yu

et al.

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

Published: Oct. 5, 2024

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers neuroinflammation and, response to different inflammatory stimuli, overexpress a proinflammatory signature genes. Among these, Ch25h is gene overexpressed brain tissue from Alzheimer's disease as well various mouse models neuroinflammation. encodes cholesterol 25-hydroxylase, an enzyme upregulated activated microglia under conditions neuroinflammation, that hydroxylates form 25-hydroxycholesterol (25HC). 25HC can be further metabolized 7α,25-dihydroxycholesterol, which potent chemoattractant leukocytes. We have previously shown increases production secretion cytokine, IL-1β, by primary treated with lipopolysaccharide (LPS). In present study, wildtype (WT) Ch25h-knockout (KO) mice were peripherally administered LPS induce state brain. LPS-treated WT mice, expression levels increased relative vehicle-treated mice. females produced significantly higher showed transcriptomic changes reflecting cytokine leukocyte migration than male However, similar males among KO Ch25h-deficiency coincided decreased microglial activation systemic LPS. Proinflammatory intra-parenchymal infiltration leukocytes lower compared Amounts IL-1β IL-6 strongly correlated levels. Our results suggest role for following peripheral administration

Language: Английский

Citations

2
Lingering Effects of Early Institutional Rearing and Cytomegalovirus Infection on the Natural Killer Cell Repertoire of Adopted Adolescents DOI Creative Commons
Elizabeth K. Wood, Brie M. Reid,

Dagna Sheerar

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 456 - 456

Published: April 9, 2024

Adversity during infancy can affect neurobehavioral development and perturb the maturation of physiological systems. Dysregulated immune inflammatory responses contribute to many later effects on health. Whether normalization occur following a transition more nurturing, benevolent conditions is unclear. To assess potential for recovery, blood samples were obtained from 45 adolescents adopted by supportive families after impoverished infancies in institutional settings (post-institutionalized, PI). Their profiles compared 39 age-matched controls raised their biological parents (non-adopted, NA). Leukocytes immunophenotyped, this analysis focuses natural killer (NK) cell populations circulation. Cytomegalovirus (CMV) seropositivity was evaluated determine if early infection contributed impact an atypical rearing. Associations with tumor necrosis factor-alpha (TNF-α) interferon-gamma (IFN-γ), two cytokines released activated NK cells, examined. Compared NA controls, PI had lower percent CD56bright cells circulation, higher TNF-α levels, likely be infected CMV. who latent carriers CMV expressed NKG2C CD57 surface markers including CD56dim lineages. The repertoire revealed lingering rearing while still maintaining overall integrity resilience.

Language: Английский

Citations

1
Dysbiosis–epigenetics–immune system interaction and ageing health problems DOI
Sima Ataollahi Eshkoor,

Sara Fanijavadi

Journal of Medical Microbiology, Journal Year: 2024, Volume and Issue: 73(11)

Published: Nov. 28, 2024

An erratum of this article has been published full details can be found at 10.1099/jmm.0.001961 Background. The growing interest in microbiota–epigenetics–immune system research stems from the understanding that microbiota, a group micro-organisms colonized human body, influence gene expression through epigenetic mechanisms and interaction with immune system. Epigenetics refers to changes activity are not caused by alteration DNA sequence itself. Discussion. clinical significance lies potential develop new therapies for diseases linked imbalance these microbial species (dysbiosis), such as cancer neurodegenerative diseases. intricate between microbiota epigenetics involves production metabolites signalling molecules impact our health influencing responses, metabolism inflammation. Understanding interactions could lead novel therapeutic strategies targeting microbiota–epigenetic pathways improve outcomes. Conclusion. In context, we aim review emphasize current knowledge key concepts link function, exploring their relevance development maintenance homeostasis susceptibility different later life. We elucidate concerning effects among gut epigenetics, ageing dysbiosis.

Language: Английский

Citations

1
25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation DOI Creative Commons
Johnathan Romero, Danira Toral-Ríos, Jinsheng Yu

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Abstract Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers neuroinflammation response to different inflammatory stimuli overexpress a proinflammatory signature genes. Among these, Ch25h is gene overexpressed brain tissue from Alzheimer’s disease as well various mouse models neuroinflammation. encodes cholesterol 25-hydroxylase, an enzyme upregulated activated microglia under conditions neuroinflammation, hydroxylates form 25-hydroxycholesterol (25HC). 25HC can be further metabolized 7α,25-dihydroxycholesterol, which potent chemoattractant for leukocytes. We have previously shown that increases production secretion cytokine, IL-1β, by primary treated with lipopolysaccharide (LPS). In present study, wildtype (WT) Ch25h-knockout (CKO) mice were peripherally administered LPS induce state brain. LPS-treated WT mice, expression levels increased relative vehicle-treated mice. WT females produced significantly higher showed transcriptomic changes reflecting cytokine leukocyte migration than male However, similar males among CKO Ch25h-deficiency coincided decreased microglial activation systemic LPS. Proinflammatory intra-parenchymal infiltration leukocytes lower compared Amounts IL-1b IL-6 strongly correlated levels. Our results suggest role following peripheral administration

Language: Английский

Citations

0
Longitudinal analysis of peripheral immune cells in patients with multiple sclerosis treated with anti‐CD20 therapy DOI Creative Commons
Mie Rye Wæde, Lasse F. Voss,

Christina Kingo

et al.

Annals of Clinical and Translational Neurology, Journal Year: 2024, Volume and Issue: 11(10), P. 2657 - 2672

Published: Sept. 15, 2024

Abstract Objective Anti‐CD20 therapy is a highly effective treatment for multiple sclerosis (MS). In this study, we investigated MS‐related changes in peripheral blood mononuclear cell (PBMC) subsets compared to healthy controls and longitudinal related the treatment. Methods Multicolor spectral flow cytometry analysis was performed on 78 samples characterize disease‐ treatment‐related PBMC clusters. Blood from MS patients were collected at baseline up 8 months post‐treatment, with three collection points after initiation. Unsupervised clustering tools manual gating applied identify subclusters of interest quantify changes. Results B cells depleted periphery anti‐CD20 as expected, observed an isolated acute, transitory drop proportion natural killer (NK) NKT among main populations ( P = 0.03, 0.004). Major affected subpopulations cytotoxic immune (NK, NKT, CD8 + T cells), higher reduced brain‐homing ability regulatory function long‐term anti‐CD20‐related effect. Additionally, altered distributions memory exhaustion markers both CD4 cells. Interpretation The findings study elucidate phenotypic clusters NK cells, which have previously been underexplored context therapy. Phenotypic modifications towards more controlled phenotype suggest that these may play critical unrecognized role mediating therapeutic efficacy treatments.

Language: Английский

Citations

0
Systems immunology insights into brain metastasis DOI Creative Commons

Wenjuan Dong,

Jianting Sheng,

Jianxiong Cui

et al.

Trends in Immunology, Journal Year: 2024, Volume and Issue: 45(11), P. 903 - 916

Published: Oct. 22, 2024

Brain metastasis poses formidable clinical challenges due to its intricate interactions with the brain's unique immune environment, often resulting in poor prognoses. This review delves into systems immunology's role uncovering dynamic interplay between metastatic cancer cells and brain immunity. Leveraging spatial single-cell technologies, along advanced computational modeling, immunology offers unprecedented insights mechanisms of evasion tumor proliferation. Recent studies highlight potential immunotherapeutic targets, suggesting strategies boost antitumor immunity counteract cell brain. Despite substantial progress, persist, particularly accurately simulating human conditions. underscores need for interdisciplinary collaboration harness full potential, aiming dramatically improve outcomes patients metastasis.

Language: Английский

Citations

0