Journal of Neuroinflammation最新文献

{"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}

{"title":"Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states.","authors":"Rebecca K John, Sadie P Vogel, Sameera Zia, Kelly V Lee, Antoinette T Nguyen, Abel Torres-Espin, Keith K Fenrich, Carmen Ng, Emma K A Schmidt, Romana Vavrek, Pamela J F Raposo, Keira Smith, Karim Fouad, Jason R Plemel","doi":"10.1186/s12974-025-03379-6","DOIUrl":"10.1186/s12974-025-03379-6","url":null,"abstract":"<p><strong>Background: </strong>Rehabilitative training is an effective method to promote recovery following spinal cord injury (SCI), with lower training efficacy observed in the chronic stage. The increased training efficacy during the subacute period is associated with a shift towards a more adaptive or proreparative state induced by the SCI. A potential link is SCI-induced inflammation, which is elevated in the subacute period, and, as injection of lipopolysaccharide (LPS) alongside training improves recovery in chronic SCI, suggesting LPS could reopen a window of plasticity late after injury. Microglia may play a role in LPS-mediated plasticity as they react to LPS and are implicated in facilitating recovery following SCI. However, it is unknown how microglia change in response to LPS following SCI to promote neuroplasticity.</p><p><strong>Main body: </strong>Here we used single-cell RNA sequencing to examine microglial responses in subacute and chronic SCI with and without an LPS injection. We show that subacute SCI is characterized by a disease-associated microglial (DAM) signature, while chronic SCI is highly heterogeneous, with both injury-induced and homeostatic states. DAM states exhibit predicted metabolic pathway activity and neuronal interactions that are associated with potential mediators of plasticity. With LPS injection, microglia shifted away from the homeostatic signature to a primed, translation-associated state and increased DAM in degenerated tracts caudal to the injury.</p><p><strong>Conclusion: </strong>Microglial states following an inflammatory stimulus in chronic injury incompletely recapitulate the subacute injury environment, showing both overlapping and distinct microglial signatures across time and with LPS injection. Our results contribute to an understanding of how microglia and LPS-induced neuroinflammation contribute to plasticity following SCI.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"56"},"PeriodicalIF":9.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531518","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":"Protective role of mitophagy on microglia-mediated neuroinflammatory injury through mtDNA-STING signaling in manganese-induced parkinsonism.","authors":"Yang Lu, Liang Gao, Yuqing Yang, Dihang Shi, Zhipeng Zhang, Xiaobai Wang, Ying Huang, Jie Wu, Jia Meng, Hong Li, Dongying Yan","doi":"10.1186/s12974-025-03396-5","DOIUrl":"10.1186/s12974-025-03396-5","url":null,"abstract":"<p><p>Manganese (Mn), the third most abundant transition metal in the earth's crust, has widespread applications in the emerging field of organometallic catalysis and traditional industries. Excessive Mn exposure causes neurological syndrome resembling Parkinson's disease (PD). The pathogenesis of PD is thought to involve microglia-mediated neuroinflammatory injury, with mitochondrial dysfunction playing a role in aberrant microglial activation. In the early stages of PD, PINK1/Parkin-mediated mitophagy contributes to the microglial inflammatory response via the cGAS/STING signaling pathway. Suppression of PINK1/Parkin-mediated mitophagy due to excessive Mn exposure exacerbates neuronal injury. Moreover, excessive Mn exposure leads to neuroinflammatory damage via the microglial cGAS-STING pathway. However, the precise role of microglial mitophagy in modulating neuroinflammation in Mn-induced parkinsonism and its underlying molecular mechanism remains unclear. Here, we observed that Mn-exposed mice exhibited neurobehavioral abnormalities and detrimental microglial activation, along with increased apoptosis of nerve cells, proinflammatory cytokines, and intracellular ROS. Furthermore, in vivo and in vitro experiments showed that excessive Mn exposure resulted in microglial mitochondrial dysfunction, manifested by increased mitochondrial ROS, decreased mitochondrial mass, and membrane potential. Additionally, with the escalating Mn dose, PINK1/Parkin-mediated mitophagy changed from activation to suppression. This was evidenced by decreased levels of LC3-II, PINK1, p-Parkin/Parkin, and increased levels of p62 protein expression level, as well as the colocalization between ATPB and LC3B due to excessive Mn exposure. Upregulation of mitophagy by urolithin A could mitigate Mn-induced mitochondrial dysfunction, as indicated by decreased mitochondrial ROS, increased mitochondrial mass, and membrane potential, along with improvements in neurobehavioral deficits and attenuated detrimental microglial activation. Using single-nucleus RNA-sequencing (snRNA-seq) analysis in the Mn-exposed mouse model, we identified the microglial cGAS-STING signaling pathway as a potential mechanism underlying Mn-induced neuroinflammation. This pathway is associated with an increase in cytosolic mtDNA levels, which activate STING signaling. These findings point to the induction of microglial mitophagy as a viable strategy to alleviate Mn-induced neuroinflammation through mtDNA-STING signaling.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"55"},"PeriodicalIF":9.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531514","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":"Myelin-reactive CD8⁺ T cells influence conventional dendritic cell subsets towards a mature and regulatory phenotype in experimental autoimmune encephalomyelitis.","authors":"Mohit Upadhye, Connor R Wilhelm, Kai J Rogers, Chakrapani Vemulawada, Nicholas Borcherding, Alexander W Boyden, Kevin L Legge, Nitin J Karandikar","doi":"10.1186/s12974-025-03377-8","DOIUrl":"10.1186/s12974-025-03377-8","url":null,"abstract":"<p><p>Multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system, is modeled in mice as experimental autoimmune encephalomyelitis (EAE). While CD4⁺ T cells, primarily Th1 and Th17 subsets, drive disease pathogenesis, the exact function of CD8⁺ T cells remains unclear. We previously demonstrated that adoptively transferred myelin-reactive CD8⁺ T cells (PLP-CD8) prevent EAE induction and suppress ongoing disease through the engagement of MHC Class-I in recipient mice. Here, we show that PLP-CD8 induce regulatory changes in both subsets of conventional dendritic cells (cDC1 and CD11b⁺ cDC) in vivo and in vitro. Adoptively transferred PLP-CD8 promoted both cDC subsets to adopt a mature and regulatory phenotype with an anti-inflammatory cytokine profile and a reduced capacity to support CD4⁺ T cell proliferation. In vitro, PLP-CD8 induced similar phenotypic changes in both cDC subsets in an antigen-specific, dose-dependent manner. PLP-CD8 directly interacted with cDC1 and indirectly influenced CD11b⁺ cDC through paracrine signaling. Notably, direct interaction with PLP-CD8 had detrimental effects on CD11b⁺ cDC. Single-cell RNA sequencing revealed upregulation of key immunoregulatory genes, such as Foxo3, in both cDC subsets with enrichment of pathways involved in immune regulation and T cell differentiation. Our study highlights a novel mechanism in which myelin-reactive CD8⁺ T cells directly interact with cDC1 and modulate CD11b⁺ cDC through paracrine mechanisms to induce mature, regulatory dendritic cells, which leads to inhibited CD4⁺ T cell responses and reduced EAE pathogenesis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"54"},"PeriodicalIF":9.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531502","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":"Prenatal inflammation exacerbates hyperoxia-induced neonatal brain injury.","authors":"Meray Serdar, Kay-Anja Walther, Markus Gallert, Karina Kempe, Stefanie Obst, Nicole Labusek, Ralf Herrmann, Josephine Herz, Ursula Felderhoff-Müser, Ivo Bendix","doi":"10.1186/s12974-025-03389-4","DOIUrl":"10.1186/s12974-025-03389-4","url":null,"abstract":"<p><strong>Background: </strong>Premature born infants are at high risk to develop white matter injury (WMI). Hyperoxia and perinatal inflammation are main risk factors for preterm birth and associated brain injury. To date the majority of experimental studies have focused on isolated insults. However, clinically, WMI injury is a multifactorial disorder caused by a variety of triggers. To establish a clinically relevant rodent model of WMI, we combined prenatal inflammation with postnatal hyperoxia to investigate individual, and additive or synergistic effects on inflammatory processes, myelination and grey matter development.</p><p><strong>Methods: </strong>At embryonic day 20, pregnant Wistar rat dams received either a single intraperitoneal injection of 100 µg/ kg lipopolysaccharide (LPS) or sodium chloride. Offspring were either exposed to hyperoxia (80% O₂) or normoxia (21% O₂) from postnatal day 3 to 5. Animals were sacrificed immediately after hyperoxia or 6 days later, corresponding to term-equivalent age. White and grey matter development and neuroinflammatory responses were investigated at cellular and molecular levels applying immunohistochemistry, western blotting, real time PCR in brain tissues and multiplex protein expression analysis on serum samples.</p><p><strong>Results: </strong>Prenatal inflammation combined with postnatal hyperoxia resulted in reduced body weight and length in the offspring, accompanied by increased serum leptin levels at term equivalent age. The altered body parameters, like body weight, were associated with decreased brain volume, thinning of deep cortical layers and hypomyelination. As potential underlying mechanisms, we identified severe myelination deficits and an increased microglia activation associated with elevated inflammatory cytokine expression in brain tissues, while peripheral cytokine levels were reduced. Interestingly, effects on body size were mainly mediated by prenatal LPS, independent of hyperoxia, while oligodendrocyte degeneration was mainly induced by postnatal hyperoxia, independent of prenatal inflammation. However, for the majority of pathological changes, including brain size, myelination deficits, microglia activation and inflammatory cytokine expression, additive or synergistic effects were detected.</p><p><strong>Conclusion: </strong>Prenatal inflammation combined with postnatal hyperoxia results in aggravated myelination deficits and inflammatory responses compared to single insults, making it an ideal model to improve our understanding of the complex pathophysiology underlying WMI and to evaluate urgently needed therapies.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"57"},"PeriodicalIF":9.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531535","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":"Integration and functionality of human iPSC-derived microglia in a chimeric mouse retinal model.","authors":"Chun Tang, Qi-Qi Zhou, Xiu-Feng Huang, Ya-Yi Ju, Bi-Lin Rao, Zhi-Cong Liu, Yi-An Jia, Zhan-Pei Bai, Qing-Yang Lin, Lin Liu, Jia Qu, Jun Zhang, Mei-Ling Gao","doi":"10.1186/s12974-025-03393-8","DOIUrl":"10.1186/s12974-025-03393-8","url":null,"abstract":"<p><strong>Introduction: </strong>Microglia, the resident immune cells of the central nervous system, play a pivotal role in maintaining homeostasis, responding to injury, and modulating neuroinflammation. However, the limitations of rodent models in accurately representing human microglia have posed significant challenges in the study of retinal diseases.</p><p><strong>Methods: </strong>PLX5622 was used to eliminate endogenous microglia in mice through oral and intraperitoneal administration, followed by transplantation of human induced pluripotent stem cell-derived microglia (hiPSC-microglia, iMG) into retinal explants to create a novel ex vivo chimeric model containing xenotransplanted microglia (xMG). The number and proportion of xMG in the retina were quantified using retinal flat-mounting and immunostaining. To evaluate the proliferative capacity and synaptic pruning ability of xMG, the expression of Ki-67 and the phagocytosis of synaptic proteins SV2 and PSD95 was assessed. The chimeric model was stimulated with LPS, and single-cell RNA sequencing (scRNA-seq) was used to analyze transcriptomic changes in iMG and xMG. Mouse IL-34 antibody neutralization experiments were performed, and the behavior of xMG in retinal degenerative Pde6b^-/- mice was examined.</p><p><strong>Results: </strong>We demonstrated that xenotransplanted microglia (xMG) successfully migrated to and localized within the mouse retina, adopting homeostatic morphologies. Our approach achieved over 86% integration of human microglia, which maintained key functions including proliferation, immune responsiveness, and synaptic pruning over a 14-day culture period. scRNA-seq of xMG revealed a shift in microglial signatures compared to monoculture iMG, indicating a transition to a more in vivo-like phenotype. In retinal degenerative Pde6b^-/- mice, xMG exhibited activation and migrated toward degenerated photoreceptors.</p><p><strong>Conclusion: </strong>This model provides a powerful platform for studying human microglia in the retinal context, offering significant insights for advancing research into retinal degenerative diseases and developing potential therapeutic strategies. Future applications of this model include using patient-derived iPSCs to investigate disease-specific microglial behaviors, thereby enhancing our understanding of microglia-related pathogenesis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"53"},"PeriodicalIF":9.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523720","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":"Inhibition of IL-6 trans-signaling promotes post-stroke functional recovery in a sex and dose-dependent manner.","authors":"Cassandra Hall, Dustin T Nguyen, Kate Mendoza, Chunfeng Tan, Anjali Chauhan","doi":"10.1186/s12974-025-03365-y","DOIUrl":"10.1186/s12974-025-03365-y","url":null,"abstract":"<p><strong>Introduction: </strong>Elevated circulating IL-6 levels are associated with poorer outcomes after stroke, and increased serum IL-6 levels are linked to a higher risk of stroke. IL-6 binds to soluble IL-6 receptors (sIL-6R) and subsequently to ubiquitously expressed gp130, initiating proinflammatory trans-signaling. This study tested the hypothesis that inhibiting IL-6 trans-signaling by administering soluble (s) gp130 improves long-term functional outcomes in young mice after stroke.</p><p><strong>Methods: </strong>Recombinant mouse gp130Fc chimera (sgp130) was administered one hour after middle cerebral artery occlusion (MCAO) followed by twice-weekly administration for 2 weeks in mice (8-15 weeks old). Behavioral assessments were done on days 7 and 28 post-MCAO for chronic studies. Flow cytometry was performed on days 3 (blood) and 7 (spleen and brain) to assess IL-6, mIL-6R, and phosphorylated STAT3 expression.</p><p><strong>Results: </strong>Improved long-term functional outcomes were observed in male, but not female mice. To investigate the differential response in females, ELISA analyses revealed that plasma IL-6 levels increased in both sexes after MCAO, with a more pronounced induction in females. Additionally, circulating sIL-6R levels were significantly higher in females compared to males (p < 0.05) at 24 h post-MCAO. Administering a higher dose of sgp130 (1 mg/kg) to females improved long-term functional outcomes, suggesting that a higher dose is needed to inhibit IL-6 trans-signaling in females effectively. Mechanistically, sgp130 treatment reduced phosphorylated STAT3 expression in brain F4/80 macrophages and increased the expression of mIL-6R on splenic immune cells at day 7 post-MCAO in both sexes.</p><p><strong>Conclusion: </strong>These findings demonstrate that inhibition of IL-6 trans-signaling with gp130Fc improves long-term functional outcomes in both male and female mice, albeit in a dose-dependent manner. This study provides novel insights into potential therapeutic strategies targeting IL-6 signaling pathways following stroke.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"52"},"PeriodicalIF":9.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515953","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}