Journal of Neuroinflammation最新文献

{"title":"H3K18 lactylation-mediated nucleotide-binding oligomerization domain-2 (NOD2) expression promotes bilirubin-induced pyroptosis of astrocytes.","authors":"Jing Li, Siyu Li, Qian Sun, Ling Li, Yan Zhang, Ziyu Hua","doi":"10.1186/s12974-025-03399-2","DOIUrl":"10.1186/s12974-025-03399-2","url":null,"abstract":"<p><p>Histone lactylation, a newly glycosis-related histone modification, plays a crucial role in the regulation of gene expression in various immune cells. However, the role of histone lactylation in astrocytes remains unclear. Here, this study showed that the H3K18 lactylation (H3K18la) levels were upregulated in primary astrocytes under unconjugated bilirubin (UCB) stimulation and hippocampus of bilirubin encephalopathy (BE) rats. Inhibition of glycolysis decreased H3K18la and attenuated pyroptosis both in vitro and in vivo. CUT& Tag and RNA-seq results revealed that H3K18la was enriched at the promoter of nucleotide-binding oligomerization domain 2 (NOD2) and promoted its transcription. Moreover, NOD2 boosted the activation of downstream mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, which exacerbated the neuroinflammation of BE. Collectively, this study provides a novel understanding of epigenetic regulation in astrocytes, and interruption of the H3K18la/NOD2 axis may represent a novel therapeutic strategy for treating bilirubin encephalopathy.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"76"},"PeriodicalIF":9.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615585","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":"Beyond the itch: the complex interplay of immune, neurological, and psychological factors in chronic urticaria.","authors":"Shurui Yang, Li Chen, Haiming Zhang, Yanjuan Song, Wenyan Wang, Zhengbo Hu, Siyu Wang, Liuyang Huang, Yayuan Wang, Song Wu, Rui Chen, Fengxia Liang","doi":"10.1186/s12974-025-03397-4","DOIUrl":"10.1186/s12974-025-03397-4","url":null,"abstract":"<p><p>Chronic urticaria (CU) arises from a multifaceted interplay of immunological, neurological, and psychological components. Immune dysregulation, mediated through both immunoglobulin E (IgE)-dependent and IgE-independent pathways, plays a pivotal role in CU pathogenesis, involving key effector cells such as mast cells (MCs), basophils, and eosinophils. This dysregulation culminates in the release of histamine, prostaglandins, and other mediators, which precipitate pruritus. The chronicity of the disease leads to sustained pruritic symptoms, contributing to both central and peripheral sensitization. The excitation of the itch circuit is augmented, leading to the release of neurotransmitters and neuropeptides, which subsequently interact with immune cells. Psychological factors such as depression, anxiety, and stress exacerbate CU symptoms and diminish quality of life. These factors disrupt the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS). Furthermore, the act of scratching activates the reward circuit, resulting in the manifestation of the itch-scratching cycle. Current treatments, such as antihistamines, omalizumab, and cyclosporine, demonstrate variable efficacy and are often associated with adverse effects. A holistic approach addressing both psychological and physiological aspects is advocated. This review highlights the critical importance of understanding neuroimmune interactions and the influence of psychosomatic factors in CU. It aims to enhance diagnostic and therapeutic strategies by integrating psychological, neurological, and immunological perspectives.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"75"},"PeriodicalIF":9.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604942","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 histone deacetylase 6 alleviates neuropathic pain via direct regulating post-translation of spinal STAT3 and decreasing downstream C-C Motif Chemokine Ligand 7 synthesis.","authors":"Zhexi Chi, Bo Lu, Rongjun Liu, Chen Pan, Bo Meng, Xiuzhong Xing, Hui Yuan, Xuewei Wu, Yushan Chen, Yuxuan Ren, Wenwei Wu, Mengmeng Miao, Junping Chen, Xiaowei Chen","doi":"10.1186/s12974-025-03400-y","DOIUrl":"10.1186/s12974-025-03400-y","url":null,"abstract":"<p><p>Neuropathic pain, a debilitating nerve injury-induced condition, remains a significant clinical challenge. This study evaluates the effect of histone deacetylase 6 (HDAC6) inhibition in a spared nerve injury (SNI) mouse model. Systemic administration of the selective HDAC6 inhibitor ACY-1215 (20 mg/kg/day, 14 days), alleviated SNI-induced pain in mice of both sexes. ACY-1215 increased acetylated signal transducer and activator of transcription 3 (Ac-STAT3) and reduced phosphorylated STAT3 (p-STAT3) in the lumbar spinal cord of SNI mice. HDAC6 and p-STAT3 were expressed in spinal dorsal horn neurons, and SNI-enhanced HDAC6/STAT3 interaction was reversed by ACY-1215. Neuronal STAT3 overexpression induced pain hypersensitivity and elevated p-STAT3, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), effects suppressed by ACY-1215. Cytokine profiling identified CC-chemokine ligand 7 (CCL7) as a key downstream effector of the HDAC6/STAT3 axis, with ACY-1215 attenuating SNI-induced CCL7 upregulation. HDAC6 knockdown in neurons reduced p-STAT3, while HDAC6 or STAT3 knockdown diminished CCL7 production. These findings demonstrate that ACY-1215 mitigates neuropathic pain by modulating STAT3 acetylation/phosphorylation and suppressing HDAC6/STAT3-driven CCL7 and cytokine release. This study underscores the role of the HDAC6/STAT3/CCL7 signaling axis in neuropathic pain and highlights the therapeutic potential of HDAC6 inhibitors for pain management.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"74"},"PeriodicalIF":9.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605215","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":"Neuroinflammation causes mitral cell dysfunction and olfactory impairment in a multiple sclerosis model.","authors":"Charlotte Schubert, Kristina Schulz, Jana K Sonner, Alexandros Hadjilaou, Anna-Lena Seemann, Janine Gierke, Vanessa Vieira, Nina Meurs, Marcel S Woo, Christian Lohr, Fabio Morellini, Daniela Hirnet, Manuel A Friese","doi":"10.1186/s12974-025-03388-5","DOIUrl":"10.1186/s12974-025-03388-5","url":null,"abstract":"<p><strong>Background: </strong>Olfactory dysfunction is an underestimated symptom in multiple sclerosis (MS). Here, we examined the pathogenic mechanisms underlying inflammation-induced dysfunction of the olfactory bulb using the animal model of MS, experimental autoimmune encephalomyelitis (EAE).</p><p><strong>Results: </strong>Reduced olfactory function in EAE was associated with the degeneration of short-axon neurons, immature neurons, and both mitral and tufted cells, along with their synaptic interactions and axonal repertoire. To dissect the mechanisms underlying the susceptibility of mitral cells, the main projection neurons of the olfactory bulb, we profiled their responses to neuroinflammation by single-nucleus RNA sequencing followed by functional validation. Neuroinflammation resulted in the induction of potassium channel transcripts in mitral cells, which was reflected in increased halothane-induced outward currents of these cells, likely contributing to the impaired olfaction in EAE animals.</p><p><strong>Conclusion: </strong>This study reveals the crucial role of mitral cells and their potassium channel activity in the olfactory bulb during EAE, thereby enhancing our understanding of neuroinflammation-induced neurodegeneration in MS.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"71"},"PeriodicalIF":9.3,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586006","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":"Intravitreal delivery of NMO-IgG causes primary retinal damage in the absence of optic nerve injury.","authors":"Biyue Chen, Huanfen Zhou, Mingming Sun, Wanqun Yang, Qianqian Li, Kaishu Yang, Honglu Song, Quangang Xu, Xintong Xu, Yuyu Li, Yanyan Yu, Shihui Wei, Tingjun Chen","doi":"10.1186/s12974-025-03380-z","DOIUrl":"10.1186/s12974-025-03380-z","url":null,"abstract":"<p><strong>Background: </strong>Neuromyelitis Optica (NMO) is a neuroimmune disorder primarily driven by autoantibodies against aquaporin 4 (AQP4), known as NMO-IgG. Although the mechanisms underlying NMO-IgG-induced retinopathy are not fully understood, the high expression of AQP4 in retinal Müller cells suggests a direct interaction that may trigger inflammatory processes in the retina. Previous studies indicate that microglia play a critical role in mediating immune responses, leading to neuronal dysfunction.</p><p><strong>Methods: </strong>NMO-IgG obtained from clinical patients was administered via intravitreal injection to female C57BL/6 mice. Techniques such as optical coherence tomography (OCT), Flash Visual Evoked Potential (f-VEP), electroretinography (ERG), real-time fluorescence quantitative PCR (RT-qPCR), and immunofluorescence analyses were used to assess retinal changes. The potential for reversing retinopathy was explored by depleting microglial cells using the CSF1 receptor inhibitor PLX3397. Additionally, a Transwell co-culture system of MIO-M1 (Müller cells) and BV2 (microglia) cells was established to study their interactions.</p><p><strong>Results: </strong>Intravitreal injection of purified NMO-IgG in mouse models led to its deposition in the retina and downregulation of AQP4 in provided. Vascular leakage was observed, alongside retinal dysfunction characterized by thinning of the retinal nerve fiber layer (RNFL) and loss of retinal ganglion cells (RGCs). On day 7, C3 expression was upregulated in Müller cells, followed by microglial activation. Significant morphological changes in microglia were noted, with increased expression of iNOS and C1q, indicating substantial activation. Ablating microglia significantly mitigated NMO-IgG-induced injury to RGCs. In vitro, NMO-IgG-treated MIO-M1 cells secreted higher levels of C3, enhancing the activation and migration of BV2 cells compared to controls.</p><p><strong>Conclusions: </strong>The retinal dysfunction observed in NMO may primarily be linked to the activation of Müller cells by NMO-IgG, leading to increased C3 secretion, which in turn activates microglia. Therapeutic strategies targeting Müller cell-microglia interactions in NMO-IgG-induced retinopathy could be promising in addressing the underlying retinal pathology in this condition.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"69"},"PeriodicalIF":9.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585995","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 role of myeloid cell heterogeneity during spontaneous choroidal neovascularization in Vldlr knockout mice.","authors":"Amrita Rajesh, Joyce Gong, Kyle S Chan, Ritvik Viniak, Steven Droho, David Kachar, Joshua Y Strauss, Andrew L Wang, Jeremy A Lavine","doi":"10.1186/s12974-025-03398-3","DOIUrl":"10.1186/s12974-025-03398-3","url":null,"abstract":"<p><strong>Background: </strong>Myeloid cells are heterogeneous cells that are critical for spontaneous choroidal neovascularization (CNV) in the Vldlr^-/- mouse model. However, the specific myeloid cell subtype necessary for CNV remains unknown.</p><p><strong>Methods and results: </strong>To investigate the role of monocytes, we bred Ccr2^-/- and Nr4a1^-/- mice into the Vldlr^-/- background. We found that Ccr2 and Nr4a1 deficiency had no effect upon macrophage counts, CNV lesion number, or total CNV area. Next, we investigated the role of microglia by generating Vldlr^-/-Tmem119^CreER/+Rosa26^DTR/+ mice. Diphtheria toxin (DT) treatment reduced macrophage counts at CNV lesions and CNV lesion number, but did not affect total CNV lesion area. To target microglia via a second strategy, we generated Vldlr^-/-Cx3cr1^CreERCsf1r^iDTR mice and treated them with a single low dose of tamoxifen to target microglia without affecting choroidal macrophages. DT treatment in Vldlr^-/-Cx3cr1^CreERCsf1r^iDTR mice decreased macrophage counts at CNV lesions and CNV lesion number but again had no effect upon total CNV lesion area. To target choroidal macrophages and microglia, we treated Vldlr^-/-Cx3cr1^CreERCsf1r^iDTR mice with 9 tamoxifen treatments. DT-treated mice showed dramatic reductions in macrophage counts, CNV number, and total lesion area.</p><p><strong>Conclusions: </strong>These data suggest that monocytes and monocyte-derived macrophages are dispensable, microglia are likely initiators for CNV development, and choroidal macrophages are potential key contributors to CNV growth and/or maintenance in the Vldlr^-/- model.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"70"},"PeriodicalIF":9.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586022","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":"Microglial progranulin differently regulates hypothalamic lysosomal function in lean and obese conditions via cleavage-dependent mechanisms.","authors":"Chae Beom Park, Chan Hee Lee, Gil Myoung Kang, Se Hee Min, Min-Seon Kim","doi":"10.1186/s12974-025-03370-1","DOIUrl":"10.1186/s12974-025-03370-1","url":null,"abstract":"<p><p>Progranulin (PGRN) is a secretory precursor protein composed of 7.5 granulins (GRNs). Mutations in the PGRN-encoding gene Grn have been associated with neurodegenerative diseases. In our previous study, we found that Grn depletion in microglia disrupted glucose metabolism in mice fed a normal chow diet (NCD) but prevented the development of obesity in mice on a high-fat diet (HFD). Given that PGRN regulates lysosomal functions, we investigated lysosomal changes in the hypothalamus of mice with microglia-specific Grn depletion. Here we report that microglia-specific Grn depletion affects the lysosomes of hypothalamic proopiomelanocortin (POMC) neurons and microglia in diet-dependent fashion. Under NCD conditions, microglial Grn depletion led to increased lysosome mass, reduced lysosomal degradative capacity, and accumulation of lipofuscin and cytoplasmic TDP-43 in hypothalamic cells, indicative of lysosomal stress and dysfunction. In contrast, under HFD conditions, the absence of microglial Grn suppressed HFD-induced hypothalamic lysosomal stress. In cultured hypothalamic neurons and microglia, PGRN treatment enhanced lysosomal function, an effect inhibited by PGRN cleavage but restored when its cleavage was blocked. Since HFD feeding promotes the cleavage of hypothalamic PGRN into multi-GRNs and GRNs, the diet-dependent lysosomal changes observed in microglial Grn-depleted mice may be linked to PGRN cleavage. We also demonstrated that intracerebroventricular injection of bafilomycin, which induces lysosomal stress, resulted in microglial activation, inflammation, disrupted POMC neuronal circuitry, and impaired leptin signaling in the hypothalamus-common features of obesity. Our results indicate that microglial PGRN plays an important role in maintaining hypothalamic lysosomal function under healthy diet conditions, whereas increased cleavage of microglial PGRN in states of overnutrition disrupts hypothalamic lysosomal function, thereby fostering hypothalamic inflammation and obesity.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"68"},"PeriodicalIF":9.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586003","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":"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}