Journal of Neuroinflammation最新文献

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Interleukin-2 improves insulin sensitivity through hypothalamic sympathetic activation in obese mice. 白细胞介素-2 通过激活下丘脑交感神经改善肥胖小鼠的胰岛素敏感性。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-10-04 DOI: 10.1186/s12974-024-03244-y
Subin Moon, Yejin Park, Sooyeon Jang, Saeha Kim, Dan-Gyeong Song, Dae-Chul Shin, Chan Hee Lee
{"title":"Interleukin-2 improves insulin sensitivity through hypothalamic sympathetic activation in obese mice.","authors":"Subin Moon, Yejin Park, Sooyeon Jang, Saeha Kim, Dan-Gyeong Song, Dae-Chul Shin, Chan Hee Lee","doi":"10.1186/s12974-024-03244-y","DOIUrl":"10.1186/s12974-024-03244-y","url":null,"abstract":"<p><strong>Background: </strong>IL-2 regulates T cell differentiation: low-dose IL-2 induces immunoregulatory Treg differentiation, while high-dose IL-2 acts as a potent activator of cytotoxic T cells and NK cells. Therefore, high-dose IL-2 has been studied for use in cancer immunotherapy. We aimed to utilize low-dose IL-2 to treat inflammatory diseases such as obesity and insulin resistance, which involve low-grade chronic inflammation.</p><p><strong>Main body: </strong>Systemic administration of low-dose IL-2 increased Treg cells and decreased inflammation in gonadal white adipose tissue (gWAT), leading to improved insulin sensitivity in high-fat diet-fed obese mice. Additionally, central administration of IL-2 significantly enhanced insulin sensitivity through the activation of the sympathetic nervous system. The sympathetic signaling induced by central IL-2 administration not only decreased interferon γ (IFNγ) + Th1 cells and the expression of pro-inflammatory cytokines, including Il-1β, Il-6, and Il-8, but also increased CD4 + CD25 + FoxP3 + Treg cells and Tgfβ expression in the gWAT of obese mice. These phenomena were accompanied by hypothalamic microgliosis and activation of pro-opiomelanocortin neurons. Furthermore, sympathetic denervation in gWAT reversed the enhanced insulin sensitivity and immune cell polarization induced by central IL-2 administration.</p><p><strong>Conclusion: </strong>Overall, we demonstrated that IL-2 improves insulin sensitivity through two mechanisms: direct action on CD4 + T cells and via the neuro-immune axis triggered by hypothalamic microgliosis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"250"},"PeriodicalIF":9.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11453069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tracking changes in functionality and morphology of repopulated microglia in young and old mice. 跟踪年轻和年老小鼠中重新填充的小胶质细胞的功能和形态变化。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-10-03 DOI: 10.1186/s12974-024-03242-0
Zuzanna M Luczak-Sobotkowska, Patrycja Rosa, Maria Banqueri Lopez, Natalia Ochocka, Anna Kiryk, Anna M Lenkiewicz, Martin Furhmann, Aleksander Jankowski, Bozena Kaminska
{"title":"Tracking changes in functionality and morphology of repopulated microglia in young and old mice.","authors":"Zuzanna M Luczak-Sobotkowska, Patrycja Rosa, Maria Banqueri Lopez, Natalia Ochocka, Anna Kiryk, Anna M Lenkiewicz, Martin Furhmann, Aleksander Jankowski, Bozena Kaminska","doi":"10.1186/s12974-024-03242-0","DOIUrl":"10.1186/s12974-024-03242-0","url":null,"abstract":"<p><strong>Background: </strong>Microglia (MG) are myeloid cells of the central nervous system that support homeostasis and instigate neuroinflammation in pathologies. Single-cell RNA sequencing (scRNA-seq) revealed the functional heterogeneity of MG in mouse brains. Microglia are self-renewing cells and inhibition of colony-stimulating factor 1 receptor (CSF1R) signaling depletes microglia which rapidly repopulate. The functions of repopulated microglia are poorly known.</p><p><strong>Methods: </strong>We combined scRNA-seq, bulk RNA-seq, immunofluorescence, and confocal imaging to study the functionalities and morphology of repopulated microglia.</p><p><strong>Results: </strong>A CSRF1R inhibitor (BLZ-945) depleted microglia within 21 days and a number of microglia was fully restored within 7 days, as confirmed by TMEM119 staining and flow cytometry. ScRNA-seq and computational analyses demonstrate that repopulated microglia originated from preexisting progenitors and reconstituted functional clusters but upregulated inflammatory genes. Percentages of proliferating, immature microglia displaying inflammatory gene expression increased in aging mice. Morphometric analysis of MG cell body and branching revealed a distinct morphology of repopulated MG, particularly in brains of old mice. We demonstrate that with aging some repopulated MG fail to reach the homeostatic phenotype. These differences may contribute to the deterioration of MG protective functions with age.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"248"},"PeriodicalIF":9.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mast cells promote choroidal neovascularization in a model of age-related macular degeneration. 在老年性黄斑变性模型中,肥大细胞促进脉络膜新生血管形成。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-10-01 DOI: 10.1186/s12974-024-03229-x
Rabah Dabouz, Pénélope Abram, Jose Carlos Rivera, Sylvain Chemtob
{"title":"Mast cells promote choroidal neovascularization in a model of age-related macular degeneration.","authors":"Rabah Dabouz, Pénélope Abram, Jose Carlos Rivera, Sylvain Chemtob","doi":"10.1186/s12974-024-03229-x","DOIUrl":"10.1186/s12974-024-03229-x","url":null,"abstract":"<p><p>'Wet' age-related macular degeneration (AMD) is characterized by pathologic choroidal neovascularization (CNV) that destroys central vision. Abundant evidence points to inflammation and immune cell dysfunction in the progression of CNV in AMD. Mast cells are resident immune cells that control the inflammatory response. Mast cells accumulate and degranulate in the choroid of patients with AMD, suggesting they play a role in CNV. Activated mast cells secrete various biologically active mediators, including inflammatory cytokines and proteolytic enzymes such as tryptase. We investigated the role of mast cells in AMD using a model of CNV. Conditioned media from activated mast cells exerts proangiogenic effects on choroidal endothelial cells and choroidal explants. Laser-induced CNV in vivo was markedly attenuated in mice genetically depleted of mast cells (Kit<sup>W-sh/W-sh</sup>) and in wild-type mice treated with mast cell stabilizer, ketotifen fumarate. Tryptase was found to elicit pronounced choroidal endothelial cell sprouting, migration and tubulogenesis; while tryptase inhibition diminished CNV. Transcriptomic analysis of laser-treated RPE/choroid complex revealed collagen catabolism and extracellular matrix (ECM) reorganization as significant events correlated in clusters of mast cell activation. Consistent with these analyses, compared to wildtype mice choroids of laser-treated mast cell-deficient mice displayed less ECM remodelling evaluated using collagen hybridizing peptide tissue binding. Findings herein provide strong support for mast cells as key players in the progression of pathologic choroidal angiogenesis and as potential therapeutic targets to prevent pathological neovascularization in 'wet' AMD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"247"},"PeriodicalIF":9.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exercise training upregulates CD55 to suppress complement-mediated synaptic phagocytosis in Parkinson's disease. 运动训练可上调 CD55,从而抑制帕金森病患者补体介导的突触吞噬。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-09-28 DOI: 10.1186/s12974-024-03234-0
Hongkai Yao, Weifang Tong, Yunping Song, Ruoyu Li, Xuerui Xiang, Wen Cheng, Yunjiao Zhou, Yijing He, Yi Yang, Yunxi Liu, Siguang Li, Lingjing Jin
{"title":"Exercise training upregulates CD55 to suppress complement-mediated synaptic phagocytosis in Parkinson's disease.","authors":"Hongkai Yao, Weifang Tong, Yunping Song, Ruoyu Li, Xuerui Xiang, Wen Cheng, Yunjiao Zhou, Yijing He, Yi Yang, Yunxi Liu, Siguang Li, Lingjing Jin","doi":"10.1186/s12974-024-03234-0","DOIUrl":"10.1186/s12974-024-03234-0","url":null,"abstract":"<p><p>The primary pathological change in Parkinson's disease (PD) is the progressive degeneration of dopaminergic neurons in the substantia nigra. Additionally, excessive microglial activation and synaptic loss are also typical features observed in PD samples. Exercise trainings have been proven to improve PD symptoms, delay the disease progression as well as affect excessive microglial synaptic phagocytosis. In this study, we established a mouse model of PD by injecting mouse-derived α-synuclein preformed fibrils (M-α-syn PFFs) into the substantia nigra, and demonstrated that treadmill exercise inhibits microglial activation and synaptic phagocytosis in striatum. Using RNA-Seq and proteomics, we also found that PD involves excessive activation of the complement pathway which is closely related to over-activation of microglia and abnormal synaptic function. More importantly, exercise training can inhibit complement levels and complement-mediated microglial phagocytosis of synapses. It is probably triggered by CD55, as we observed that CD55 in the striatum significantly increased after exercise training and up-regulation of that molecule rescued motor deficits of PD mice, accompanied with reduced microglial synaptic phagocytosis in the striatum. This research elucidated the interplay among microglia, complement, and synapses, and analyzed the effects of exercise training on these factors. Our work also suggested CD55 as a complement-relevant candidate molecule for developing therapeutic strategies of PD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"246"},"PeriodicalIF":9.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1. SIRT6通过靶向星形胶质细胞CHI3L1调节LPC诱导的脱髓鞘病变微环境。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-09-28 DOI: 10.1186/s12974-024-03241-1
Jingyi Du, Yue Yin, Dong Wu, Can Diao, Tiantian Zhao, Fan Peng, Naigang Li, Dongshuang Wang, Jiaming Shi, Liyan Wang, Liang Kong, Wenjuan Zhou, Aijun Hao
{"title":"SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.","authors":"Jingyi Du, Yue Yin, Dong Wu, Can Diao, Tiantian Zhao, Fan Peng, Naigang Li, Dongshuang Wang, Jiaming Shi, Liyan Wang, Liang Kong, Wenjuan Zhou, Aijun Hao","doi":"10.1186/s12974-024-03241-1","DOIUrl":"10.1186/s12974-024-03241-1","url":null,"abstract":"<p><p>Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"243"},"PeriodicalIF":9.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neuroinflammatory responses and blood-brain barrier injury in chronic alcohol exposure: role of purinergic P2 × 7 Receptor signaling. 慢性酒精暴露中的神经炎症反应和血脑屏障损伤:嘌呤能 P2 × 7 受体信号传导的作用。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-09-28 DOI: 10.1186/s12974-024-03230-4
Namdev S Togre, Naveen Mekala, Priyanka S Bhoj, Nikhita Mogadala, Malika Winfield, Jayshil Trivedi, Deborah Grove, Sudhir Kotnala, Slava Rom, Uma Sriram, Yuri Persidsky
{"title":"Neuroinflammatory responses and blood-brain barrier injury in chronic alcohol exposure: role of purinergic P2 × 7 Receptor signaling.","authors":"Namdev S Togre, Naveen Mekala, Priyanka S Bhoj, Nikhita Mogadala, Malika Winfield, Jayshil Trivedi, Deborah Grove, Sudhir Kotnala, Slava Rom, Uma Sriram, Yuri Persidsky","doi":"10.1186/s12974-024-03230-4","DOIUrl":"10.1186/s12974-024-03230-4","url":null,"abstract":"<p><p>Alcohol consumption leads to neuroinflammation and blood‒brain barrier (BBB) damage, resulting in neurological impairment. We previously demonstrated that ethanol-induced disruption of barrier function in human brain endothelial cells was associated with mitochondrial injury, increased ATP and extracellular vesicle (EV) release, and purinergic receptor P2 × 7R activation. Therefore, we aimed to evaluate the effect of P2 × 7R blockade on peripheral and neuro-inflammation in ethanol-exposed mice. In a chronic intermittent ethanol (CIE)-exposed mouse model, P2 × 7R was inhibited by two different methods: Brilliant Blue G (BBG) or gene knockout. We assessed blood ethanol concentration (BEC), brain microvessel gene expression by using RT2 PCR array, plasma P2 × 7R and P-gp, serum ATP, EV-ATP, number of EVs, and EV mtDNA copy numbers. An RT2 PCR array of brain microvessels revealed significant upregulation of proinflammatory genes involved in apoptosis, vasodilation, and platelet activation in CIE-exposed wild-type animals, which were decreased 15-50-fold in BBG-treated-CIE-exposed animals. Plasma P-gp levels and serum P2 × 7R shedding were significantly increased in CIE-exposed animals. Pharmacological or genetic suppression of P2 × 7R decreased receptor shedding to levels equivalent to those in control group. The increase in EV number and EV-ATP content in the CIE-exposed mice was significantly reduced by P2 × 7R inhibition. CIE mice showed augmented EV-mtDNA copy numbers which were reduced in EVs after P2 × 7R inhibition or receptor knockout. These observations suggested that P2 × 7R signaling plays a critical role in ethanol-induced brain injury. Increased extracellular ATP, EV-ATP, EV numbers, and EV-mtDNA copy numbers highlight a new mechanism of brain injury during alcohol exposure via P2 × 7R and biomarkers of such damage. In this study, for the first time, we report the in vivo involvement of P2 × 7R signaling in CIE-induced brain injury.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"244"},"PeriodicalIF":9.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer's disease. 在阿尔茨海默病小鼠模型中,AIBP 可控制 TLR4 气体马拉松和线粒体功能障碍。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-09-28 DOI: 10.1186/s12974-024-03214-4
Yi Sak Kim, Soo-Ho Choi, Keun-Young Kim, Juliana M Navia-Pelaez, Guy A Perkins, Seunghwan Choi, Jungsu Kim, Nicolaus Nazarenkov, Robert A Rissman, Won-Kyu Ju, Mark H Ellisman, Yury I Miller
{"title":"AIBP controls TLR4 inflammarafts and mitochondrial dysfunction in a mouse model of Alzheimer's disease.","authors":"Yi Sak Kim, Soo-Ho Choi, Keun-Young Kim, Juliana M Navia-Pelaez, Guy A Perkins, Seunghwan Choi, Jungsu Kim, Nicolaus Nazarenkov, Robert A Rissman, Won-Kyu Ju, Mark H Ellisman, Yury I Miller","doi":"10.1186/s12974-024-03214-4","DOIUrl":"10.1186/s12974-024-03214-4","url":null,"abstract":"<p><p>Microglia-driven neuroinflammation plays an important role in the development of Alzheimer's disease. Microglia activation is accompanied by the formation and chronic expression of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp<sup>-/-</sup> APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased reactive oxygen species and the dilated endoplasmic reticulum. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp<sup>-/-</sup>APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in Alzheimer's disease associated oxidative stress and neurodegeneration.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"245"},"PeriodicalIF":9.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Autophagy defects at weaning impair complement-dependent synaptic pruning and induce behavior deficits. 断奶时的自噬缺陷会损害互补依赖性突触修剪并诱发行为缺陷。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-09-27 DOI: 10.1186/s12974-024-03235-z
Xi Su, Guanyu Wang, Senqi Liu, Jinming Li, Minglong Shao, Yongfeng Yang, Meng Song, Yong Han, Wenqiang Li, Luxian Lv
{"title":"Autophagy defects at weaning impair complement-dependent synaptic pruning and induce behavior deficits.","authors":"Xi Su, Guanyu Wang, Senqi Liu, Jinming Li, Minglong Shao, Yongfeng Yang, Meng Song, Yong Han, Wenqiang Li, Luxian Lv","doi":"10.1186/s12974-024-03235-z","DOIUrl":"https://doi.org/10.1186/s12974-024-03235-z","url":null,"abstract":"<p><p>Autophagy is crucial for synaptic plasticity and the architecture of dendritic spines. However, the role of autophagy in schizophrenia (SCZ) and the mechanisms through which it affects synaptic function remain unclear. In this study, we identified 995 single nucleotide polymorphisms (SNPs) across 19 autophagy-related genes that are associated with SCZ. Gene Set Enrichment Analysis (GSEA) of data from the Gene Expression Omnibus public database revealed defective autophagy in patients with SCZ. Using a maternal immune activation (MIA) rat model, we observed that autophagy was downregulated during the weaning period, and early-life activation of autophagy with rapamycin restored abnormal behaviors and electrophysiological deficits in adult rats. Additionally, inhibition of autophagy with 3-Methyladenine (3-MA) during the weaning period resulted in aberrant behaviors, abnormal electrophysiology, increased spine density, and reduced microglia-mediated synaptic pruning. Furthermore, 3-MA treatment significantly decreased the expression and synaptosomal content of complement, impaired the recognition of C3b and CR3, indicating that autophagy deficiency disrupts complement-mediated synaptic pruning. Our findings provide evidence for a significant association between SCZ and defective autophagy, highlighting a previously underappreciated role of autophagy in regulating the synaptic and behavioral deficits induced by MIA.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"239"},"PeriodicalIF":9.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tryptophan-rich diet and its effects on Htr7+ Tregs in alleviating neuroinflammation and cognitive impairment induced by lipopolysaccharide. 富含色氨酸的饮食及其对 Htr7+ Tregs 在减轻脂多糖诱导的神经炎症和认知障碍方面的影响
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-09-27 DOI: 10.1186/s12974-024-03239-9
Dinghao Xue, Xu Guo, Jingjing Liu, Yanxiang Li, Luyu Liu, Guosong Liao, Mingru Zhang, Jiangbei Cao, Yanhong Liu, Jingsheng Lou, Hao Li, Weidong Mi, Long Wang, Qiang Fu
{"title":"Tryptophan-rich diet and its effects on Htr7<sup>+</sup> Tregs in alleviating neuroinflammation and cognitive impairment induced by lipopolysaccharide.","authors":"Dinghao Xue, Xu Guo, Jingjing Liu, Yanxiang Li, Luyu Liu, Guosong Liao, Mingru Zhang, Jiangbei Cao, Yanhong Liu, Jingsheng Lou, Hao Li, Weidong Mi, Long Wang, Qiang Fu","doi":"10.1186/s12974-024-03239-9","DOIUrl":"https://doi.org/10.1186/s12974-024-03239-9","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation is a vital pathogenic mechanism for neurodegenerative diseases such as Alzheimer's, schizophrenia, and age-related cognitive decline. Regulatory T cells (Tregs) exhibit potent anti-inflammatory properties and can modulate neurodegenerative diseases arising from central nervous system inflammatory responses. However, the role of Tregs in neuroinflammation-related cognitive dysfunction remains unclear. It is highly plausible that Htr7<sup>+</sup> Tregs expressing unique genes associated with the nervous system, including the Htr7 gene encoding the serotonin receptor 5-HT<sub>7</sub>, play a pivotal role.</p><p><strong>Methods: </strong>Mice were given a tryptophan-rich diet (with a tryptophan content of 0.6%) or a normal diet (with a tryptophan content of 0.16%). The neuroinflammation-mediated cognitive dysfunction model was established by intracerebroventricular injection of lipopolysaccharide (LPS) in 8-week-old C57BL/6J mice. The activation and infiltration of Tregs were measured using flow cytometry. Primary Tregs were cocultured separately with primary CD8<sup>+</sup> T cells and primary microglia for in vitro validation of the impact of 5-HT and 5-HT<sub>7</sub> receptor on Tregs. Prior to their transfer into recombination activating gene 1 (Rag1<sup>-/-</sup>) mice, Tregs were ex vivo transfected with lentivirus to knock down the expression of Htr7.</p><p><strong>Results: </strong>In this study, the tryptophan-rich diet was found to reverse LPS-induced cognitive impairment and reduce the levels of 5-HT in peripheral blood. The tryptophan-rich diet led to increased levels of 5-HT in peripheral blood, which in turn promoted the proliferation and activation of Htr7<sup>+</sup> Tregs. Additionally, the tryptophan-rich diet was also shown to attenuate LPS-mediated neuroinflammation by activating Htr7<sup>+</sup> Tregs. Furthermore, 5-HT and 5-HT<sub>7</sub> receptor were found to enhance the immunosuppressive effect of Tregs on CD8<sup>+</sup> T cells and microglia. In Rag1<sup>-/-</sup> mice, Htr7<sup>+</sup> Tregs were shown to alleviate LPS-induced neuroinflammation and cognitive impairment.</p><p><strong>Conclusions: </strong>Our research revealed the ability of Htr7<sup>+</sup> Tregs to mitigate neuroinflammation and prevent neuronal damage by suppressing the infiltration of CD8<sup>+</sup> T cells into the brain and excessive activation of microglia, thereby ameliorating LPS-induced cognitive impairment. These insights may offer novel therapeutic targets involving Tregs for neuroinflammation and cognitive impairment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"241"},"PeriodicalIF":9.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11437714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Knockdown of microglial iron import gene, Slc11a2, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer's disease. 在阿尔茨海默病的APP/PS1模型中,敲除小胶质细胞铁导入基因Slc11a2会恶化认知功能,并以性别特异性的方式改变小胶质细胞转录景观。
IF 9.3 1区 医学
Journal of Neuroinflammation Pub Date : 2024-09-27 DOI: 10.1186/s12974-024-03238-w
Katrina Volk Robertson, Alec S Rodriguez, Jean-Philippe Cartailler, Shristi Shrestha, Michael W Schleh, Kyle R Schroeder, Arianna M Valenti, Alec T Kramer, Fiona E Harrison, Alyssa H Hasty
{"title":"Knockdown of microglial iron import gene, Slc11a2, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer's disease.","authors":"Katrina Volk Robertson, Alec S Rodriguez, Jean-Philippe Cartailler, Shristi Shrestha, Michael W Schleh, Kyle R Schroeder, Arianna M Valenti, Alec T Kramer, Fiona E Harrison, Alyssa H Hasty","doi":"10.1186/s12974-024-03238-w","DOIUrl":"10.1186/s12974-024-03238-w","url":null,"abstract":"<p><strong>Background: </strong>Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype.</p><p><strong>Methods: </strong>In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-β-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1<sup>Cre-ERT2</sup>;Slc11a2<sup>flfl</sup>;APP/PS1<sup>+or -</sup> mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted.</p><p><strong>Results: </strong>DMT1 inhibition in vitro robustly decreased Aβ-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2<sup>KD</sup> APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2<sup>KD</sup> APP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2<sup>KD</sup> cells from APP/PS1 females also exhibited decreased expression of markers associated with subsets of disease-associated microglia (DAMs), such as Apoe, Ctsb, Ly9, Csf1, and Hif1α.</p><p><strong>Conclusions: </strong>This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2<sup>KD</sup> APP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"238"},"PeriodicalIF":9.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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