Journal of Neuroinflammation最新文献

{"title":"Development of cerebral microhemorrhages in a mouse model of hypertension.","authors":"Danny F Xie, Chuo Fang, Christian Crouzet, Yu-Han Hung, Adrian Vallejo, Donghy Lee, Jihua Liu, Han Liu, Suhrith Muvvala, Annlia Paganini-Hill, Wei Ling Lau, David H Cribbs, Bernard Choi, Mark Fisher","doi":"10.1186/s12974-025-03378-7","DOIUrl":"10.1186/s12974-025-03378-7","url":null,"abstract":"<p><p>Cerebral microhemorrhages (CMH) are the pathological substrate for MRI-demonstrable cerebral microbleeds, which are associated with cognitive impairment and stroke. Aging and hypertension are the main risk factors for CMH. In this study, we investigated the development of CMH in a mouse model of aging and hypertension. Hypertension was induced in aged (17-month-old) female and male C57BL/6J mice via angiotensin II (Ang II), a potent vasoconstrictor. We investigated the vascular origin of CMH using three-dimensional images of 1-mm thick brain sections. We examined Ang II-induced CMH formation with and without telmisartan, an Ang II type 1 receptor (AT1R) blocker. To evaluate the effect of microglia and perivascular macrophages on CMH formation, mice were treated with PLX3397, a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, to achieve microglial and macrophage depletion. Iba-1 and CD206 labeling were used to study the relative contributions of microglia and macrophages, respectively, on CMH formation. CMH quantification was performed with analysis of histological sections labeled with Prussian blue. Vessels surrounding CMH were primarily of capillary size range (< 10 μm in diameter). Ang II-infused mice exhibited elevated blood pressure (p < 0.0001) and CMH burden (p < 0.001). CMH burden was significantly correlated with mean arterial pressure in mice with and without Ang II (r = 0.52, p < 0.05). Ang II infusion significantly increased Iba-1 immunoreactivity (p < 0.0001), and CMH burden was significantly correlated with Iba-1 in mice with and without Ang II (r = 0.32, p < 0.05). Telmisartan prevented elevation of blood pressure due to Ang II infusion and blocked Ang II-induced CMH formation without affecting Iba-1 immunoreactivity. PLX3397 treatment reduced Iba-1 immunoreactivity in Ang II-infused mice (p < 0.001) and blocked Ang II-induced CMH (p < 0.0001). No significant association between CMH burden and CD206 reactivity was observed. Our findings demonstrate Ang II infusion increases CMH burden. CMH in this model appear to be capillary-derived and Ang II-induced CMH are largely mediated by blood pressure. In addition, microglial activation may represent an alternate pathway for CMH formation. These observations emphasize the continuing importance of blood pressure control and the role of microglia in hemorrhagic cerebral microvascular disease.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"67"},"PeriodicalIF":9.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567202","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 protective PLCγ2-P522R variant mitigates Alzheimer's disease-associated pathologies by enhancing beneficial microglial functions.","authors":"Mari Takalo, Heli Jeskanen, Taisia Rolova, Inka Kervinen, Marianna Hellén, Sami Heikkinen, Hennariikka Koivisto, Kimmo Jokivarsi, Stephan A Müller, Esa-Mikko Koivumäki, Petra Mäkinen, Sini-Pauliina Juopperi, Roosa-Maria Willman, Rosa Sinisalo, Dorit Hoffmann, Henna Jäntti, Michael Peitz, Klaus Fließbach, Teemu Kuulasmaa, Teemu Natunen, Susanna Kemppainen, Pekka Poutiainen, Ville Leinonen, Tarja Malm, Henna Martiskainen, Alfredo Ramirez, Annakaisa Haapasalo, Stefan F Lichtenthaler, Heikki Tanila, Christian Haass, Juha Rinne, Jari Koistinaho, Mikko Hiltunen","doi":"10.1186/s12974-025-03387-6","DOIUrl":"10.1186/s12974-025-03387-6","url":null,"abstract":"<p><strong>Background: </strong>Phospholipase C gamma 2, proline 522 to arginine (PLCγ2-P522R) is a protective variant that reduces the risk of Alzheimer's disease (AD). Recently, it was shown to mitigate β-amyloid pathology in a 5XFAD mouse model of AD. Here, we investigated the protective functions of the PLCγ2-P522R variant in a less aggressive APP/PS1 mouse model of AD and assessed the underlying cellular mechanisms using mouse and human microglial models.</p><p><strong>Methods: </strong>The effects of the protective PLCγ2-P522R variant on microglial activation, AD-associated β-amyloid and neuronal pathologies, and behavioral changes were investigated in PLCγ2-P522R knock-in variant mice crossbred with APP/PS1 mice. Transcriptomic, proteomic, and functional studies were carried out using microglia isolated from mice carrying the PLCγ2-P522R variant. Finally, microglia-like cell models generated from human blood and skin biopsy samples of PLCγ2-P522R variant carriers were employed.</p><p><strong>Results: </strong>The PLCγ2-P522R variant decreased β-amyloid plaque count and coverage in female APP/PS1 mice. Moreover, the PLCγ2-P522R variant promoted anxiety in these mice. The area of the microglia around β-amyloid plaques was also increased in mice carrying the PLCγ2-P522R variant, while β-amyloid plaque-associated neuronal dystrophy and the levels of certain cytokines, including IL-6 and IL-1β, were reduced. These alterations were revealed through [18F]FEPPA PET imaging and behavioral studies, as well as various cytokine immunoassays, transcriptomic and proteomic analyses, and immunohistochemical analyses using mouse brain tissues. In cultured mouse primary microglia, the PLCγ2-P522R variant reduced the size of lipid droplets. Furthermore, transcriptomic and proteomic analyses revealed that the PLCγ2-P522R variant regulated key targets and pathways involved in lipid metabolism, mitochondrial fatty acid oxidation, and inflammatory/interferon signaling in acutely isolated adult mouse microglia and human monocyte-derived microglia-like cells. Finally, the PLCγ2-P522R variant also increased mitochondrial respiration in human iPSC-derived microglia.</p><p><strong>Conclusions: </strong>These findings suggest that the PLCγ2-P522R variant exerts protective effects against β-amyloid and neuronal pathologies by increasing microglial responsiveness to β-amyloid plaques in APP/PS1 mice. The changes observed in lipid/fatty acid and mitochondrial metabolism revealed by the omics and metabolic assessments of mouse and human microglial models suggest that the protective effects of the PLCγ2-P522R variant are potentially associated with increased metabolic capacity of microglia.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"64"},"PeriodicalIF":9.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557270","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":"Bystander neuronal progenitors in forebrain organoids promote protective antiviral responses.","authors":"Seble G Negatu, Christine Vazquez, Carl Bannerman, Kevin R Amses, Guo-Li Ming, Kellie A Jurado","doi":"10.1186/s12974-025-03381-y","DOIUrl":"10.1186/s12974-025-03381-y","url":null,"abstract":"<p><p>Neurotropic viruses are the most common cause of infectious encephalitis and highly target neurons for infection. Our understanding of the intrinsic capacity of neuronal innate immune responses to mediate protective antiviral responses remains incomplete. Here, we evaluated the role of intercellular crosstalk in mediating intrinsic neuronal immunity and its contribution to limiting viral infection. We found that in the absence of viral antagonism, neurons transcriptionally induce robust interferon signaling and can effectively signal to uninfected bystander neurons. Yet, in two-dimensional cultures, this dynamic response did not restrict viral spread. Interestingly, this differed in the context of viral infection in three-dimensional forebrain organoids with complex neuronal subtypes and cellular organization, where we observed protective capacity. We showed antiviral crosstalk between infected neurons and bystander neural progenitors is mediated by type I interferon signaling. Using spatial transcriptomics, we then uncovered regions containing bystander neural progenitors that expressed distinct antiviral genes, revealing critical underpinnings of protective antiviral responses among neuronal subtypes. These findings underscore the importance of interneuronal communication in protective antiviral immunity in the brain and implicate key contributions to protective antiviral signaling.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"65"},"PeriodicalIF":9.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567199","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":"Antiretroviral drug therapy does not reduce neuroinflammation in an HIV-1 infection brain organoid model.","authors":"Samuel Martinez-Meza, Thomas A Premeaux, Stefano M Cirigliano, Courtney M Friday, Stephanie Michael, Sonia Mediouni, Susana T Valente, Lishomwa C Ndhlovu, Howard A Fine, Robert L Furler O'Brien, Douglas F Nixon","doi":"10.1186/s12974-025-03375-w","DOIUrl":"10.1186/s12974-025-03375-w","url":null,"abstract":"<p><strong>Background: </strong>HIV-1-associated neurocognitive impairment (HIV-1-NCI) is marked by ongoing and chronic neuroinflammation with loss and decline in neuronal function even when antiretroviral drug therapy (ART) successfully suppresses viral replication. Microglia, the primary reservoirs of HIV-1 in the central nervous system (CNS), play a significant role in maintaining this neuroinflammatory state. However, understanding how chronic neuroinflammation is generated and sustained by HIV-1, or impacted by ART, is difficult due to limited access to human CNS tissue.</p><p><strong>Methods: </strong>We generated an in vitro model of admixed hematopoietic progenitor cell (HPC) derived microglia embedded into embryonic stem cell (ESC) derived Brain Organoids (BO). Microglia were infected with HIV-1 prior to co-culture. Infected microglia were co-cultured with brain organoids BOs to infiltrate the BOs and establish a model for HIV-1 infection, \"HIV-1 M-BO\". HIV-1 M-BOs were treated with ART for variable directions. HIV-1 infection was monitored with p24 ELISA and by digital droplet PCR (ddPCR). Inflammation was measured by cytokine or p-NF-kB levels using multiplex ELISA, flow cytometry and confocal microscopy.</p><p><strong>Results: </strong>HIV-1 infected microglia could be co-cultured with BOs to create a model for \"brain\" HIV-1 infection. Although HIV-1 infected microglia were the initial source of pro-inflammatory cytokines, astrocytes, neurons and neural stem cells also had increased p-NF-kB levels, along with elevated CCL2 levels in the supernatant of HIV-1 M-BOs compared to Uninfected M-BOs. ART suppressed the virus to levels below the limit of detection but did not decrease neuroinflammation.</p><p><strong>Conclusions: </strong>These findings indicate that HIV-1 infected microglia are pro-inflammatory. Although ART significantly suppressed HIV-1 levels, neuronal inflammation persisted in ART-treated HIV-1 M-BOs. Together, these findings indicate that HIV-1 infection of microglia infiltrated into BOs provides a robust in vitro model to understand the impact of HIV-1 and ART on neuroinflammation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"66"},"PeriodicalIF":9.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567196","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":"Extracellular mitochondria contribute to acute lung injury via disrupting macrophages after traumatic brain injury.","authors":"Yafan Liu, Fanjian Li, Lujia Tang, Kaifeng Pang, Yichi Zhang, Chaonan Zhang, Hui Guo, Tianrui Ma, Xiaoyang Zhang, Guili Yang, Ying Li, Zijian Zhou, Hejun Zhang, Yang Li, Ying Fu, Jianning Zhang, Jingfei Dong, Zilong Zhao","doi":"10.1186/s12974-025-03390-x","DOIUrl":"10.1186/s12974-025-03390-x","url":null,"abstract":"<p><p>Acute lung injury (ALI) is the most frequently developed complication in patients with severe traumatic brain injury (TBI), but its underlying mechanism remains poorly understood. Here, we report results from a study designed to investigate the mechanistic link between TBI and ALI in mouse models, in vitro experiments, and a patient study, specifically focusing on the role of extracellular mitochondria (exMt). We detected high levels of exMt in the alveolar lavage fluid of patients with TBI. The bronchoalveolar lavage fluid (BALF) of mice subjected to controlled cerebral cortical impact contained 4.2 ± 1.4 × 10⁴/µl of exMt. We further showed that non-injured mice infused with exMt intravenously developed pulmonary edema, perivascular accumulation of macrophages, inflammation, and dysfunction. Results from complementary in vitro experiments showed that exMt bound to and were phagocytosed by interstitial macrophages, resulting in autophagic flux reduction and activation of macrophages. The phagocytosis of exMt depended on the CD36 and dynamin mediated pathway, and activation of macrophages depended on exMt-derived reactive oxygen species. This study discovered a novel mechanism by which exMt contribute to the pathogenesis of TBI-induced ALI through macrophages, which are activated, develop dysfunctional autophagy, and become inflammatory after phagocytosis of exMt.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"63"},"PeriodicalIF":9.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557268","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":"Active Cryptococcus neoformans glucuronoxylomannan production prevents elimination of cryptococcal CNS infection in vivo.","authors":"Vanessa Enriquez, Melissa E Munzen, Luz M Porras, Claudia L Charles-Niño, Fahong Yu, Karina Alviña, Raddy L Ramos, Michael R Dores, Paola Giusti-Rodriguez, Luis R Martinez","doi":"10.1186/s12974-025-03384-9","DOIUrl":"10.1186/s12974-025-03384-9","url":null,"abstract":"<p><strong>Background: </strong>Cryptococcus neoformans (Cn) causes life-threatening meningoencephalitis in individuals with AIDS. Cn's polysaccharide capsule is mainly composed of glucuronoxylomannan (GXM) and plays a key role in the dysregulation of immunity, resistance to antifungal drugs, and systemic dissemination, including CNS invasion. Although recent studies have begun to elucidate the involvement of microglia in cryptococcosis, our knowledge of these CNS resident phagocytes in the control of cryptococcosis is limited.</p><p><strong>Methods: </strong>We investigated microglial responses to Cn infection and the effect of active capsular production by comparing wild-type H99 and acapsular mutant cap59 strains using the CX3CR1-EGFP transgenic mouse and a stereotaxic intracerebral infection model.</p><p><strong>Results: </strong>Microglia had difficulty combating Cn H99 infection. Active production and secretion of the capsular material altered the morphology and distribution of microglia around cryptococcomas or fungal brain lesions. It also affected the infiltration of peripheral immune cells to CNS fungal infection. Moreover, RNA sequencing analyses supported the importance of capsule production in immune modulation. Chemotaxis assays demonstrated that active capsular production by Cn H99, and especially GXM, impaired microglial motility and fungal phagocytosis.</p><p><strong>Conclusion: </strong>Our findings suggest that microglia may not be able to control cryptococcal CNS infection and that active capsular production and release may contribute to the progression and persistence of cerebral cryptococcosis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"61"},"PeriodicalIF":9.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557178","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":"Decoding dengue's neurological assault: insights from single-cell CNS analysis in an immunocompromised mouse model.","authors":"Minyue Qiu, Lixin Zhao, Xiaojia Li, Yipei Fan, Minchi Liu, Dong Hua, Yunkai Zhu, Yinyin Liang, Yu Zhang, Wen Xiao, Xiaofeng Xu, Jintao Li","doi":"10.1186/s12974-025-03383-w","DOIUrl":"10.1186/s12974-025-03383-w","url":null,"abstract":"<p><strong>Background: </strong>Dengue encephalitis, a severe neurological complication of dengue virus infection, is increasingly recognized for its rising incidence and significant public health burden. Despite its growing prevalence, the underlying mechanisms and effective therapeutic strategies remain poorly understood.</p><p><strong>Methods: </strong>Cellular atlas of dengue encephalitis was determined by single-nucleus RNA sequencing. Viral load of dengue virus and the level of cytokines expression was detected by RT-qPCR. The target cells of dengue virus were verified by immunofluorescence. The cytotoxic effect of CD8⁺ T cell was determined by flow cytometry, immunofluorescence, in vivo CD8⁺ T cell depletion, adoptive transfer and CCK-8-based cell viability assay. Axonal and synaptic reduction induced by dengue virus infection was demonstrated by RT-qPCR, Western blot, transmission electron microscope and immunofluorescence. Finally, motor and sensory functions of mice were detected by open field test and hot plate test, respectively.</p><p><strong>Results: </strong>In this study, we utilized single-nucleus RNA sequencing on brain tissues from a dengue-infected murine model to construct a comprehensive cellular atlas of dengue encephalitis. Our findings identify neurons, particularly inhibitory GABAergic subtypes, as the primary targets of dengue virus. Additionally, immune cell infiltration was observed, contributing to significant neurological damage. Comprehensive analyses of cell-cell communication, combined with CD8⁺ T cell depletion and transfer restoration experiments, have elucidated the critical role of CD8⁺ T cells in triggering encephalitis through their interaction with neurons. These cells infiltrate the brain from peripheral circulation, interact with neurons, and induce damage of synapse and axon, accompanied by neurological dysfunction.</p><p><strong>Conclusion: </strong>We defined cellular atlas of dengue encephalitis in mouse model and identified the primary target neuron of dengue virus. In addition, we demonstrated the significant cytotoxic effect of CD8⁺ T cell, which leads to apoptosis of neuron and neurological dysfunction of mice. Our study provides a molecular and cellular framework for understanding dengue encephalitis through advanced sequencing technologies. The insights gained serve as a foundation for future investigations into its pathogenesis and the development of targeted therapeutic approaches.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"62"},"PeriodicalIF":9.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557266","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":"How the gut microbiota impacts neurodegenerative diseases by modulating CNS immune cells.","authors":"Philipp Schaible, Julia Henschel, Daniel Erny","doi":"10.1186/s12974-025-03371-0","DOIUrl":"10.1186/s12974-025-03371-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Amyloid-β (Aβ) accumulation and neurofibrillary tangles are two key histological features resulting in progressive and irreversible neuronal loss and cognitive decline. The macrophages of the central nervous system (CNS) belong to the innate immune system and comprise parenchymal microglia and CNS-associated macrophages (CAMs) at the CNS interfaces (leptomeninges, perivascular space and choroid plexus). Microglia and CAMs have received attention as they may play a key role in disease onset and progression e. g., by clearing amyloid beta (Aβ) through phagocytosis. Genome-wide association studies (GWAS) have revealed that human microglia and CAMs express numerous risk genes for AD, further highlighting their potentially critical role in AD pathogenesis. Microglia and CAMs are tightly controlled by environmental factors, such as the host microbiota. Notably, it was further reported that the composition of the gut microbiota differed between AD patients and healthy individuals. Hence, emerging studies have analyzed the impact of gut bacteria in different preclinical mouse models for AD as well as in clinical studies, potentially enabling promising new therapeutic options.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"60"},"PeriodicalIF":9.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542359","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":"Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates.","authors":"Xiaogang Zhang, Laiqin Peng, Shuyi Kuang, Tianci Wang, Weibin Wu, Shaowen Zuo, Chunling Chen, Jiaxiu Ye, Guilang Zheng, Yuxiong Guo, Yumei He","doi":"10.1186/s12974-025-03385-8","DOIUrl":"10.1186/s12974-025-03385-8","url":null,"abstract":"<p><p>Fetal intrauterine distress (FD) during delivery can cause fetal intrauterine hypoxia, posing significant risks to the fetus, mother, and newborns. While studies highlight the role of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in neonatal diseases and tumor hypoxia, their specific involvement in newborns experiencing fetal distress during delivery (FDNB) is not well understood. Here, we found elevated PMN-MDSC activation, increased glycolysis, enhanced lactate production, and upregulated HIF-1α expression in the blood of FDNB neonates compared to healthy newborns (NNB). Importantly, PMN-MDSC levels were inversely correlated with neuron-specific enolase (NSE), a marker for neurological injury. In neonatal mice subjected to acute hypoxia, a 48-h exposure led to a shift from exacerbation to amelioration of brain damage when compared with a 24-h period. This change was associated with a reduction in microglial activation, a decrease in the expression of inflammatory factors within the microglia, alongside increased peripheral PMN-MDSC activation. Depleting PMN-MDSCs led to heightened microglial activation and aggravated brain injury. Mechanistically, enhanced activation of PMN-MDSCs promotes HIF-1α accumulation while enhancing glycolysis and lactate release, thereby mitigating neonatal brain injury. Notably, lactate supplementation in hypoxic mice rescued brain damage caused by insufficient PMN-MDSC activation due to HIF-1α deficiency. Our study clarifies the role of lactate in peripheral PMN-MDSCs after acute hypoxia and its effects on microglial activation and subsequent brain injury.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"59"},"PeriodicalIF":9.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537295","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":"cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia.","authors":"Xiangyu Ge, Xingfei Zhu, Wei Liu, Mingsen Li, Zhaotian Zhang, Ming Zou, Mi Deng, Haifeng Cui, Ziqing Chen, Li Wang, Xuebin Hu, Rong Ju, Xiangcheng Tang, Xiaoyan Ding, Lili Gong","doi":"10.1186/s12974-025-03391-w","DOIUrl":"10.1186/s12974-025-03391-w","url":null,"abstract":"<p><strong>Background: </strong>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 of cardiovascular destruction, but its impact on the neurovascular system is unclear. Here, we show that cGAMP, the endogenous STING agonist, causes iBRB breakdown and retinal degeneration thorough P2RX7-mediated transport into microglia.</p><p><strong>Methods: </strong>Extracellular cGAMP and STING pathway were determined in tissue samples from patients with proliferative DR (PDR) and db/db diabetic mice. Histological, molecular, bioinformatic and behavioral analysis accessed effects of cGAMP on iBRB. Single-cell RNA sequencing identified the primary retinal cell type responsive to cGAMP. Specific inhibitors and P2RX7-deficienct mice were used to evaluate P2RX7' role as a cGAMP transporter. The therapeutic effects of P2RX7 inhibitor were tested in db/db mice.</p><p><strong>Results: </strong>cGAMP was detected in the aqueous humor of patients with PDR and elevated in the vitreous humor with STING activation in db/db mouse retinas. cGAMP administration led to STING-dependent iBRB breakdown and neuron degeneration. Microglia were the primary cells responding to cGAMP, essential for cGAMP-induced iBRB breakdown and visual impairment. The ATP-gated P2RX7 transporter was required for cGAMP import and STING activation in retinal microglia. Contrary to previous thought that mouse P2RX7 nonselectively transports cGAMP only at extremely high ATP concentrations, human P2RX7 directly binds to cGAMP and activates STING under physiological conditions. Clinically, cGAMP-induced microglial signature was recapitulated in fibrovascular membranes from patients with PDR, with P2RX7 being predominantly expressed in microglia. Inhibiting P2RX7 reduced cGAMP-STING activation, protected iBRB and improved neuron survival in diabetic mouse retinas.</p><p><strong>Conclusions: </strong>Our study reveals a mechanism for cGAMP-mediated iBRB breakdown and suggests that targeting microglia and P2RX7 may mitigate the deleterious effects of STING activation in retinal diseases linked to iBRB impairment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"58"},"PeriodicalIF":9.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537294","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}