Journal of Neuroinflammation最新文献

{"title":"Microglial double stranded DNA accumulation induced by DNase II deficiency drives neuroinflammation and neurodegeneration.","authors":"Ling-Jie Li, Shi-Yu Liang, Xiao-Ying Sun, Jie Zhu, Xiao-Yun Niu, Xiao-Yu Du, Ya-Ru Huang, Rui-Tian Liu","doi":"10.1186/s12974-025-03333-6","DOIUrl":"10.1186/s12974-025-03333-6","url":null,"abstract":"<p><strong>Background: </strong>Deoxyribonuclease 2 (DNase II) is pivotal in the clearance of cytoplasmic double stranded DNA (dsDNA). Its deficiency incurs DNA accumulation in cytoplasm, which is a hallmark of multiple neurodegenerative diseases. Our previous study showed that neuronal DNase II deficiency drove tau hyperphosphorylation and neurodegeneration (Li et al., Transl Neurodegener 13:39, 2024). Although it has been verified that DNase II participates in type I interferons (IFN-I) mediated autoinflammation and senescence in peripheral systems, the role of microglial DNase II in neuroinflammation and neurodegenerative diseases such as Alzheimer's disease (AD) is still unknown.</p><p><strong>Methods: </strong>The levels of microglial DNase II in triple transgenic AD mice (3xTg-AD) were measured by immunohistochemistry. The cognitive performance of microglial DNase II deficient WT and AD mice was determined using the Morris water maze test, Y-maze test, novel object recognition test and open filed test. To investigate the impact of microglial DNase II deficiency on microglial morphology, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and IFN-I pathway, neuroinflammation, synapses loss, amyloid pathology and tauopathy, the levels of cGAS-STING and IFN-I pathway related protein, gliosis and proinflammatory cytokines, synaptic protein, complement protein, Aβ levels, phosphorylated tau in the brains of the microglial DNase II deficient WT and AD mice were evaluated by immunolabeling, immunoblotting, q-PCR or ELISA.</p><p><strong>Results: </strong>We found that the levels of DNase II were significantly decreased in the microglia of 3xTg-AD mice. Microglial DNase II deficiency altered microglial morphology and transcriptional signatures, activated the cGAS-STING and IFN-I pathway, initiated neuroinflammation, led to synapse loss via complement-dependent pathway, increased Aβ levels and tauopathy, and induced cognitive decline.</p><p><strong>Conclusions: </strong>Our study shows the effect of microglial DNase II deficiency and cytoplasmic accumulated dsDNA on neuroinflammation, and reveals the initiatory mechanism of AD pathology, suggesting that DNase II is a potential target for neurodegenerative diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"11"},"PeriodicalIF":9.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007007","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}

{"title":"The immunological perspective of major depressive disorder: unveiling the interactions between central and peripheral immune mechanisms.","authors":"Wenli Jiao, Jiayi Lin, Yanfang Deng, Yelin Ji, Chuoyi Liang, Sijia Wei, Xi Jing, Fengxia Yan","doi":"10.1186/s12974-024-03312-3","DOIUrl":"10.1186/s12974-024-03312-3","url":null,"abstract":"<p><p>Major depressive disorder is a prevalent mental disorder, yet its pathogenesis remains poorly understood. Accumulating evidence implicates dysregulated immune mechanisms as key contributors to depressive disorders. This review elucidates the complex interplay between peripheral and central immune components underlying depressive disorder pathology. Peripherally, systemic inflammation, gut immune dysregulation, and immune dysfunction in organs including gut, liver, spleen and adipose tissue influence brain function through neural and molecular pathways. Within the central nervous system, aberrant microglial and astrocytes activation, cytokine imbalances, and compromised blood-brain barrier integrity propagate neuroinflammation, disrupting neurotransmission, impairing neuroplasticity, and promoting neuronal injury. The crosstalk between peripheral and central immunity creates a vicious cycle exacerbating depressive neuropathology. Unraveling these multifaceted immune-mediated mechanisms provides insights into major depressive disorder's pathogenic basis and potential biomarkers and targets. Modulating both peripheral and central immune responses represent a promising multidimensional therapeutic strategy.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"10"},"PeriodicalIF":9.3,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007009","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}

{"title":"Satellite microglia: marker of traumatic brain injury and regulator of neuronal excitability.","authors":"Alicia B Feichtenbiner, Karinn Sytsma, Ryan P O'Boyle, Rhonda Mittenzwei, Heather Maioli, Kathryn P Scherpelz, Daniel D Child, Ning Li, Jeanelle Ariza Torres, Lisa Keene, Amanda Kirkland, Kimberly Howard, Caitlin Latimer, C Dirk Keene, Christopher Ransom, Amber L Nolan","doi":"10.1186/s12974-024-03328-9","DOIUrl":"10.1186/s12974-024-03328-9","url":null,"abstract":"<p><p>Traumatic brain injury is a leading cause of chronic neurologic disability and a risk factor for development of neurodegenerative disease. However, little is known regarding the pathophysiology of human traumatic brain injury, especially in the window after acute injury and the later life development of progressive neurodegenerative disease. Given the proposed mechanisms of toxic protein production and neuroinflammation as possible initiators or contributors to progressive pathology, we examined phosphorylated tau accumulation, microgliosis and astrogliosis using immunostaining in the orbitofrontal cortex, a region often vulnerable across traumatic brain injury exposures, in an age and sex-matched cohort of community traumatic brain injury including both mild and severe cases in midlife. We found that microglial response is most prominent after chronic traumatic brain injury, and interactions with neurons in the form of satellite microglia are increased, even after mild traumatic brain injury. Taking our investigation into a mouse model, we identified that these satellite microglia suppress neuronal excitability in control conditions but lose this ability with chronic traumatic brain injury. At the same time, network hyperexcitability is present in both mouse and human orbitofrontal cortex. Our findings support a role for loss of homeostatic control by satellite microglia in the maladaptive circuit changes that occur after traumatic brain injury.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"9"},"PeriodicalIF":9.3,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007008","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}

{"title":"The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity.","authors":"Daniel Torrente, Enming J Su, Alí Francisco Citalán-Madrid, Gerald P Schielke, Daniel Magaoay, Mark Warnock, Tamara Stevenson, Kris Mann, Flavie Lesept, Nathalie Delétage, Manuel Blanc, Erin H Norris, Denis Vivien, Daniel A Lawrence","doi":"10.1186/s12974-025-03336-3","DOIUrl":"10.1186/s12974-025-03336-3","url":null,"abstract":"<p><p>The thrombolytic protease tissue plasminogen activator (tPA) is expressed in the CNS, where it regulates diverse functions including neuronal plasticity, neuroinflammation, and blood-brain-barrier integrity. However, its role in different brain regions such as the substantia nigra (SN) is largely unexplored. In this study, we characterize tPA expression, activity, and localization in the SN using a combination of retrograde tracing and β-galactosidase tPA reporter mice. We further investigate tPA's potential role in SN pathology in an α-synuclein mouse model of Parkinson's disease (PD). To characterize the mechanism of tPA action in α-synuclein-mediated pathology in the SN and to identify possible therapeutic pathways, we performed RNA-seq analysis of the SN and used multiple transgenic mouse models. These included tPA deficient mice and two newly developed transgenic mice, a knock-in model expressing endogenous levels of proteolytically inactive tPA (tPA Ala-KI) and a second model overexpressing proteolytically inactive tPA (tPA Ala-BAC). Our findings show that striatal GABAergic neurons send tPA⁺ projections to dopaminergic (DA)-neurons in the SN and that tPA is released from SN-derived synaptosomes upon stimulation. We also found that tPA levels in the SN increased following α-synuclein overexpression. Importantly, tPA deficiency protects DA-neurons from degeneration, prevents behavioral deficits, and reduces microglia activation and T-cell infiltration induced by α-synuclein overexpression. RNA-seq analysis indicates that tPA in the SN is required for the upregulation of genes involved in the innate and adaptive immune responses induced by α-synuclein overexpression. Overexpression of α-synuclein in tPA Ala-KI mice, expressing only proteolytically inactive tPA, confirms that tPA-mediated neuroinflammation and neurodegeneration is independent of its proteolytic activity. Moreover, overexpression of proteolytically inactive tPA in tPA Ala-BAC mice leads to increased neuroinflammation and neurodegeneration compared to mice expressing normal levels of tPA, suggesting a tPA dose response. Finally, treatment of mice with glunomab, a neutralizing antibody that selectively blocks tPA binding to the N-methyl-D-aspartate receptor-1 (NMDAR1) without affecting NMDAR1 ion channel function, identifies the tPA interaction with NMDAR1 as necessary for tPA-mediated neuroinflammation and neurodegeneration in response to α-synuclein-mediated neurotoxicity. Thus, our data identifies a novel pathway that promotes DA-neuron degeneration and suggests a potential therapeutic intervention for PD targeting the tPA-NMDAR1 interaction.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"8"},"PeriodicalIF":9.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055809","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}

{"title":"TREM2 affects DAM-like cell transformation in the acute phase of TBI in mice by regulating microglial glycolysis.","authors":"Lin Wang, Diqing Ouyang, Lin Li, Yunchuan Cao, Yingwen Wang, Nina Gu, Zhaosi Zhang, Zhao Li, Shuang Tang, Hui Tang, Yuan Zhang, Xiaochuan Sun, Jin Yan","doi":"10.1186/s12974-025-03337-2","DOIUrl":"10.1186/s12974-025-03337-2","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) is characterized by high mortality and disability rates. Disease-associated microglia (DAM) are a newly discovered subtype of microglia. However, their presence and function in the acute phase of TBI remain unclear. Although glycolysis is important for microglial differentiation, its regulatory role in DAM transformation during the acute phase of TBI is still unclear. In this study, we investigated the functions of DAM-like cells in the acute phase of TBI in mice, as well as the relationship between their transformation and glycolysis.</p><p><strong>Methods: </strong>In this study, a controlled cortical impact model was used to induce TBI in adult male wild-type (WT) C57BL/6 mice and adult male TREM2 knockout mice. Various techniques were used to assess the role of DAM-like cells in TBI and the effects of glycolysis on DAM-like cells, including RT‒qPCR, immunofluorescence assays, behavioural tests, extracellular acidification rate (ECAR) tests, Western blot analysis, cell magnetic sorting and culture, glucose and lactate assays, and flow cytometry.</p><p><strong>Results: </strong>DAM-like cells were observed in the acute phase of TBI in mice, and their transformation depended on TREM2 expression. TREM2 knockout impaired neurological recovery in TBI mice, possibly due in part to their role in clearing debris and secreting VEGFa and BDNF. Moreover, DAM-like cells exhibited significantly increased glycolytic activity. TREM2 regulated the AKT‒mTOR‒HIF-1α pathway and glycolysis in microglia in the acute phase of TBI. The increase in glycolysis in microglia partially contributed to the transformation of DAM-like cells in the acute phase of TBI in mice.</p><p><strong>Conclusions: </strong>Taken together, the results of our study demonstrated that DAM-like cells were present in the acute phase of TBI in mice. TREM2 might influence DAM-like cell transformation by modulating the glycolysis of microglia. Our results provide a new possible pathway for intervening TBI.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"6"},"PeriodicalIF":9.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971093","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}

{"title":"Lipid droplets in central nervous system and functional profiles of brain cells containing lipid droplets in various diseases.","authors":"Longxiao Zhang, Yunfei Zhou, Zhongbo Yang, Liangchao Jiang, Xinyang Yan, Wenkai Zhu, Yi Shen, Bolong Wang, Jiaxi Li, Jinning Song","doi":"10.1186/s12974-025-03334-5","DOIUrl":"10.1186/s12974-025-03334-5","url":null,"abstract":"<p><p>Lipid droplets (LDs), serving as the convergence point of energy metabolism and multiple signaling pathways, have garnered increasing attention in recent years. Different cell types within the central nervous system (CNS) can regulate energy metabolism to generate or degrade LDs in response to diverse pathological stimuli. This article provides a comprehensive review on the composition of LDs in CNS, their generation and degradation processes, their interaction mechanisms with mitochondria, the distribution among different cell types, and the roles played by these cells-particularly microglia and astrocytes-in various prevalent neurological disorders. Additionally, we also emphasize the paradoxical role of LDs in post-cerebral ischemia inflammation and explore potential underlying mechanisms, aiming to identify novel therapeutic targets for this disease.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"7"},"PeriodicalIF":9.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978979","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}

{"title":"Infection with Toxoplasma gondii triggers coagulation at the blood-brain barrier and a reduction in cerebral blood flow.","authors":"Evelyn M Hoover, Christine A Schneider, Christian Crouzet, Tatiane S Lima, Dario X Figueroa Velez, Cuong J Tran, Dritan Agalliu, Sunil P Gandhi, Bernard Choi, Melissa B Lodoen","doi":"10.1186/s12974-024-03330-1","DOIUrl":"10.1186/s12974-024-03330-1","url":null,"abstract":"<p><strong>Background: </strong>Immunothrombosis is the process by which the coagulation cascade interacts with the innate immune system to control infection. However, the formation of clots within the brain vasculature can be detrimental to the host. Recent work has demonstrated that Toxoplasma gondii infects and lyses central nervous system (CNS) endothelial cells that form the blood-brain barrier (BBB). However, little is known about the effect of T. gondii infection on the BBB and the functional consequences of infection on cerebral blood flow (CBF) during the different stages of infection.</p><p><strong>Main body: </strong>We demonstrate that brain endothelial cells upregulate the adhesion molecules ICAM-1 and VCAM-1 and become morphologically more tortuous during acute T. gondii infection of mice. Longitudinal two-photon imaging of cerebral blood vessels during infection in mice revealed vascular occlusion in the brain, prompting an analysis of the coagulation cascade. We detected platelet-fibrin clots within the cerebral vasculature during acute infection. Analysis of CBF using longitudinal laser-speckle imaging during T. gondii infection demonstrated that CBF decreased during acute infection, recovered during stable chronic infection, and decreased again during reactivation of the infection induced by IFN-γ depletion. Finally, we demonstrate that treatment of mice with a low-molecular-weight heparin, an anticoagulant, during infection partially rescued CBF in T. gondii-infected mice without affecting parasite burden.</p><p><strong>Conclusions: </strong>Our data provide insight into the host-pathogen interactions of a CNS parasite within the brain vasculature and suggest that thrombosis and changes in cerebral hemodynamics may be an unappreciated aspect of infection with T. gondii.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"3"},"PeriodicalIF":9.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11708167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950329","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}

{"title":"Chemerin-9 is neuroprotective in APP/PS1 transgenic mice by inhibiting NLRP3 inflammasome and promoting microglial clearance of Aβ.","authors":"Jiawei Zhang, Yaxuan Zhang, Lan Liu, Mengyuan Zhang, Xiaojie Zhang, Jiangshan Deng, Fei Zhao, Qing Lin, Xue Zheng, Bing Fu, Yuwu Zhao, Xiuzhe Wang","doi":"10.1186/s12974-024-03325-y","DOIUrl":"10.1186/s12974-024-03325-y","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a prevalent neurodegenerative disorder worldwide, and microglia are thought to play a central role in neuroinflammatory events occurring in AD. Chemerin, an adipokine, has been implicated in inflammatory diseases and central nervous system disorders, yet its precise function on microglial response in AD remains unknown.</p><p><strong>Methods: </strong>The APP/PS1 mice were treated with different dosages of chemerin-9 (30 and 60 µg/kg), a bioactive nonapeptide derived from chemerin, every other day for 8 weeks consecutively. The primary mouse microglia were stimulated by amyloid beta 42 (Aβ₄₂) oligomers followed by treatment with chemerin-9 in vitro. ChemR23 inhibitor α-NETA was further used to investigate whether the effects of chemerin-9 were ChemR23-dependent.</p><p><strong>Results: </strong>We found that the expression of chemerin and ChemR23 was increased in AD. Intriguingly, treatment with chemerin-9 significantly ameliorated Aβ deposition and cognitive impairment of the APP/PS1 mice, with decreased microglial proinflammatory activity and increased phagocytic activity. Similarly, chemerin-9-treated primary microglia showed increased phagocytic ability and decreased NLRP3 inflammasome activation. However, the ChemR23 inhibitor α-NETA abolished the neuroprotective microglial response of chemerin-9.</p><p><strong>Conclusions: </strong>Collectively, our data demonstrate that chemerin-9 ameliorates cognitive deficits in APP/PS1 transgenic mice by boosting a neuroprotective microglial phenotype.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"5"},"PeriodicalIF":9.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11716275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950328","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}

{"title":"Shift work schedules alter immune cell regulation and accelerate cognitive impairment during aging.","authors":"Karienn A de Souza, Morgan Jackson, Justin Chen, Jocelin Reyes, Judy Muayad, Emma Tran, William Jackson, M Karen Newell-Rogers, David J Earnest","doi":"10.1186/s12974-024-03324-z","DOIUrl":"10.1186/s12974-024-03324-z","url":null,"abstract":"<p><strong>Background: </strong>Disturbances of the sleep-wake cycle and other circadian rhythms typically precede the age-related deficits in learning and memory, suggesting that these alterations in circadian timekeeping may contribute to the progressive cognitive decline during aging. The present study examined the role of immune cell activation and inflammation in the link between circadian rhythm dysregulation and cognitive impairment in aging.</p><p><strong>Methods: </strong>C57Bl/6J mice were exposed to shifted light-dark (LD) cycles (12 h advance/5d) during early adulthood (from ≈ 4-6mo) or continuously to a \"fixed\" LD12:12 schedule. At middle age (13-14mo), the long-term effects of circadian rhythm dysregulation on cognitive performance, immune cell regulation and hippocampal microglia were analyzed using behavioral, flow cytometry and immunohistochemical assays.</p><p><strong>Results: </strong>Entrainment of the activity rhythm was stable in all mice on a fixed LD 12:12 cycle but was fully compromised during exposure to shifted LD cycles. Even during \"post-treatment\" exposure to standard LD 12:12 conditions, re-entrainment in shifted LD mice was marked by altered patterns of entrainment and increased day-to-day variability in activity onset times that persisted into middle-age. These alterations in light-dark entrainment were closely associated with dramatic impairment in the Barnes maze test for the entire group of shifted LD mice at middle age, well before cognitive decline was first observed in aged (18-22mo) animals maintained on fixed LD cycles. In conjunction with the effects of circadian dysregulation on cognition, shifted LD mice at middle age were distinguished by significant expansion of splenic B cells and B cell subtypes expressing the activation marker CD69 or inflammatory marker MHC Class II Invariant peptide (CLIP), differential increases in CLIP+, 41BB-Ligand+, and CD74 + B cells in the meningeal lymphatics, alterations in splenic T cell subtypes, and increased number and altered functional state of microglia in the dentate gyrus. In shifted LD mice, the expansion in splenic B cells was negatively correlated with cognitive performance; when B cell numbers were higher, performance was worse in the Barnes maze. These results indicate that disordered circadian timekeeping associated with early exposure to shift work-like schedules alone accelerates cognitive decline during aging in conjunction with altered regulation of immune cells and microglia in the brain.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"4"},"PeriodicalIF":9.3,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11716134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950330","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}

{"title":"Complement inhibition targets a rich-club within the neuroinflammatory network after stroke to improve radiographic and functional outcomes.","authors":"Youssef M Zohdy, Tomas Garzon-Muvdi, Jonathan A Grossberg, Daniel L Barrow, Brian M Howard, Gustavo Pradilla, Firas H Kobeissy, Stephen Tomlinson, Ali M Alawieh","doi":"10.1186/s12974-024-03316-z","DOIUrl":"10.1186/s12974-024-03316-z","url":null,"abstract":"<p><p>Following recent advances in post-thrombectomy stroke care, the role of neuroinflammation and neuroprotective strategies in mitigating secondary injury has gained prominence. Yet, while neuroprotection and anti-inflammatory agents have re-emerged in clinical trials, their success has been limited. The neuroinflammatory response in cerebral ischemia is robust and multifactorial, complicating therapeutic approaches targeting single pathways. In this study, we aimed to characterize early inflammatory gene dysregulation following ischemic stroke using translational in-silico and in-vivo approaches. Using an in vivo ischemic stroke model, transcriptomic analysis revealed significant dysregulation of inflammatory genes. Graph theory analysis then showed a rich-club organization among stroke-related genes, with highly connected core nodes. The expression levels of the core genes identified within this network significantly explained radiological outcomes, including T2-signal hyperintensity (R² = 0.57, P < 0.001), mean diffusivity (R² = 0.52, P < 0.001), and mean kurtosis (R² = 0.65, P < 0.001), correlating more strongly than non-core genes. Similar findings were observed with functional and cognitive outcomes, showing R² values of 0.58, 0.7, 0.54, and 0.7 for neurological severity scores, corner tasks, passive avoidance, and novel object recognition tasks, respectively (P < 0.001). Using in-silico analysis, we identified a set of upstream regulators directly interacting with core network nodes, leading to simulations that highlighted C3-targeted therapy as a potential treatment. This hypothesis was then confirmed in vivo using a targeted C3 inhibitor (CR2-fH), which reversed gene dysregulation in the neuroinflammatory network and improved radiological and functional outcomes. Our findings underscore the significance of neuroinflammation in stroke pathology, supporting network-based therapeutic targeting and demonstrating the benefits of targeted complement inhibition in enhancing outcomes through modulation of the neuroinflammatory network core. This study's approach, combining graph theory analysis along with in-silico modeling, offers a promising translational pipeline applicable to stroke and other complex diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"1"},"PeriodicalIF":9.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926918","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}