Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus CNS infection

时间分辨单细胞RNA测序揭示单纯疱疹病毒中枢神经系统感染期间的保护性和病理性反应

Herpes Simplex Virus 1 (HSV-1) is a neurotropic virus causing encephalitis and post-infectious complications. Infections can induce a range of acute, subacute, and progressing brain disease, and in recent years it has emerged that immune responses are involved in the pathogenesis of these diseases. This study identifies a unique population of virus-activated microglia with antiviral and proinflammatory properties and reveals monocytes to be a key driver of interactions driving pathology in the virus-infected brain.

单纯疱疹病毒 1 型（HSV - 1）是一种嗜神经性病毒，可引发脑炎和感染后并发症。感染可诱发一系列急性、亚急性和进展性脑部疾病，近年来研究发现，免疫反应参与了这些疾病的发病机制。本研究鉴定出了一类具有抗病毒和促炎特性、被病毒激活的独特小胶质细胞群，并揭示单核细胞是病毒感染脑部时驱动病理过程相互作用的关键因素。

REF: Ding X, Lai X, Klaestrup IH, et al. Temporally resolved single-cell RNA sequencing reveals protective and pathological responses during herpes simplex virus CNS infection. J Neuroinflammation. 2025;22(1):146. Published 2025 May 31. doi:10.1186/s12974-025-03471-x PMID: 40450318 PMCID: PMC12125739

Astrocyte-derived extracellular vesicular NFIA mediates obesity-associated cognitive impairment

星形胶质细胞来源的细胞外囊泡核因子IA介导肥胖相关的认知障碍

The escalating global prevalence of cognitive decline associated with obesity represents a significant public health challenge. Emerging evidence implicates astrocyte-derived extracellular vesicles (ADEVs) as key mediators in the pathogenesis of neurodegenerative disease, positioning them as potential therapeutic targets. However, the precise mechanistic role of ADEVs in the pathological processes underlying obesity-related cognitive impairment remains poorly understood. The findings demonstrated that elevated levels of NFIA packaged within ADEVs contributed to hippocampal synaptic injury under obesity-induced stress condition. The mechanistic insight may provide potential therapeutic targets for addressing obesity-related cognitive decline.

与肥胖相关的认知能力下降在全球范围内日益普遍，这对公共卫生构成了重大挑战。越来越多的证据表明，星形胶质细胞来源的细胞外囊泡（ADEVs）是神经退行性疾病发病机制中的关键介质，使其成为潜在的治疗靶点。然而，ADEVs在肥胖相关认知障碍的病理过程中的确切机制作用仍知之甚少。研究结果表明，在肥胖诱导的应激条件下，ADEVs中包裹的核因子IA（NFIA）水平升高会导致海马突触损伤。这一机制方面的新认识可能为解决肥胖相关的认知能力下降提供潜在的治疗靶点。

REF: Wu L, Deng L, Xu X, et al. Astrocyte-derived extracellular vesicular NFIA mediates obesity-associated cognitive impairment. J Neuroinflammation. 2025;22(1):145. Published 2025 May 30. doi:10.1186/s12974-025-03473-9 PMID: 40448146 PMCID: PMC12125936

Impaired membrane lipids in ischemic stroke: a key player in inflammation and thrombosis

缺血性卒中中受损的膜脂：炎症和血栓形成的关键因素

Membrane lipids play a crucial role in brain function and cell signalling, and they serve as key biological substrates in inflammatory responses, thrombosis, and energy metabolism. Multiple clinical and molecular evidences suggest that membrane lipids are probably involved in the pathogenesis of ischemic stroke (IS). However, current knowledge about the membrane lipid landscape and its involvement in IS pathophysiology is limited. Our findings reveal impaired erythrocyte membrane lipid homeostasis in IS, which implicates inflammatory processes and thrombosis in IS. This research offers new insights into the role of membrane lipids in IS pathogenesis, potentially informing future monitoring and therapeutic strategies.

膜脂在大脑功能和细胞信号传导中起着至关重要的作用，并且它们是炎症反应、血栓形成和能量代谢中的关键生物底物。多项临床和分子证据表明，膜脂可能参与了缺血性中风（IS）的发病机制。然而，目前关于膜脂特征及其在缺血性中风病理生理学中的作用的认识有限。我们的研究结果揭示了缺血性中风患者红细胞膜脂稳态受损，这表明炎症过程和血栓形成与缺血性中风有关。这项研究为膜脂在缺血性中风发病机制中的作用提供了新的见解，有可能为未来的监测和治疗策略提供参考。

REF: Wang Q, Wang D, Gao Y, et al. Impaired membrane lipids in ischemic stroke: a key player in inflammation and thrombosis. J Neuroinflammation. 2025;22(1):144. Published 2025 May 28. doi:10.1186/s12974-025-03464-w PMID: 40437490 PMCID: PMC12117946

Semaglultide targets Spp1+ microglia/macrophage to attenuate neuroinflammation following perioperative stroke

司美格鲁肽靶向Spp1+小胶质细胞/巨噬细胞以减轻围手术期卒中后的神经炎症

Peripheral surgery evokes neuroimmune activation in the central nervous system and modulates immune cell polarization in the ischemic brain. However, the phenotypic change of microglia and myeloid cells within post-surgical ischemic brain tissue remain poorly defined. Using an integrated approach that combines single-cell RNA sequencing with comprehensive biological analysis in a perioperative ischemic stroke (PIS) model, we identified a distinct Spp1-positive macrophage/microglia (Spp1+ Mac/MG) subgroup that exhibit enriched anti-inflammatory pathways with distinct lipid metabolic reprogrammed profile. Moreover, using immunofluorescence staining, we identified the expression of Glucagon-like peptide-1 receptor (GLP1R) in Spp1+F4/80+ cells and Spp1+Iba-1+ cells. Intraperitoneal administration of semaglutide, a GLP1R agonist clinically approved for the treatment of type 2 diabetes mellitus, resulted in a significant reduction of cerebral infarct volume in PIS mice compared to that in ischemic stroke (IS) mice. Meanwhile, semaglutide treatment also increased the proportion of Spp1+Edu+Iba-1+ cells 3 days after PIS. Using high-parameter flow cytometry, immunofluorescence staining and RNA sequencing, we demonstrated that semaglutide treatment significantly attenuated the expression of neuroinflammatory markers in mice following PIS. We also found that semaglutide treatment significantly ameliorated sensorimotor dysfunction up to 3 days after PIS in mice. Our current finding reveal a novel protective Spp1+Mac/MG subset after PIS and demonstrated that it can be upregulated by semaglutide. We propose that targeting Spp1+Mac/MG subsets using semaglutide could serve as a promising strategy to attenuate the exacerbated neuroinflammation in PIS.

外周手术会引发中枢神经系统的神经免疫激活，并调节缺血性脑内免疫细胞的极化。然而，术后缺血性脑组织中小胶质细胞和髓系细胞的表型变化仍不明确。在围手术期缺血性卒中（PIS）模型中，我们采用单细胞RNA测序与全面生物学分析相结合的综合方法，鉴定出一个独特的骨桥蛋白（Spp1）阳性巨噬细胞/小胶质细胞（Spp1+ Mac/MG）亚群，该亚群具有丰富的抗炎通路和独特的脂质代谢重编程特征。此外，通过免疫荧光染色，我们在Spp1+F4/80+细胞和Spp1+离子钙结合衔接分子1（Iba - 1）+细胞中检测到胰高血糖素样肽 - 1受体（GLP1R）的表达。腹腔注射司美格鲁肽（一种临床批准用于治疗2型糖尿病的GLP1R激动剂）后，与缺血性卒中（IS）小鼠相比，PIS小鼠的脑梗死体积显著减小。同时，在PIS发生3天后，司美格鲁肽治疗还增加了Spp1+5 - 乙炔基 - 2’ - 脱氧尿苷（Edu）+Iba - 1+细胞的比例。通过高参数流式细胞术、免疫荧光染色和RNA测序，我们证实司美格鲁肽治疗显著降低了PIS小鼠神经炎症标志物的表达。我们还发现，司美格鲁肽治疗可显著改善PIS小鼠术后3天内的感觉运动功能障碍。我们目前的研究发现揭示了PIS后一种新的具有保护作用的Spp1+Mac/MG亚群，并证实司美格鲁肽可上调该亚群。我们提出，使用司美格鲁肽靶向Spp1+Mac/MG亚群可能是减轻PIS中加剧的神经炎症的一种有前景的策略。

REF: Li Y, Fan Q, Pang R, et al. Semaglultide targets Spp1+ microglia/macrophage to attenuate neuroinflammation following perioperative stroke. J Neuroinflammation. 2025;22(1):143. Published 2025 May 27. doi:10.1186/s12974-025-03465-9 PMID: 40426210 PMCID: PMC12117698

Endothelial TREM-1 mediates sepsis-induced blood‒brain barrier disruption and cognitive impairment via the PI3K/Akt pathway

内皮细胞髓系细胞触发受体-1（TREM - 1）通过PI3K/Akt信号通路介导脓毒症诱导的血脑屏障破坏和认知障碍

The blood‒brain barrier (BBB) is a critical selective interface between the central nervous system (CNS) and the blood circulation. BBB dysfunction plays an important role in the neurological damage caused by sepsis. However, the mechanisms underlying the disruption of the BBB during sepsis remain unclear. We established a human induced pluripotent stem cell (iPSC)-derived BBB model and reported that treating with sepsis patient serum leads to structural and functional disruption of the BBB. In a cecal ligation and puncture (CLP)-induced mouse model of sepsis, we also observed disruption of the BBB, inflammation in the brain, and impairments in cognition. In both models, we found that the expression of TREM-1 was significantly increased in endothelial cells. TREM-1 knockout specifically in endothelial cells alleviated BBB dysfunction and cognitive impairments. Further study revealed that TREM-1 affects the expression of genes involved in the PI3K/Akt signaling pathway. The protective effects of TREM-1 inhibition on the BBB and cognition were abrogated by PI3K inhibitors. Our findings suggest that endothelial TREM-1 induces sepsis-induced BBB disruption and cognitive impairments via the PI3K/Akt signaling pathway. Targeting endothelial TREM-1 or the PI3K/Akt signaling pathway may be a promising strategy to maintain BBB integrity and improve cognitive function in sepsis patients.

血脑屏障（BBB）是中枢神经系统（CNS）与血液循环之间至关重要的选择性界面。血脑屏障功能障碍在脓毒症导致的神经损伤中起着重要作用。然而，脓毒症期间血脑屏障破坏的潜在机制仍不清楚。我们建立了一个人类诱导多能干细胞（iPSC）来源的血脑屏障模型，并发现用脓毒症患者血清处理会导致血脑屏障的结构和功能破坏。在盲肠结扎穿孔（CLP）诱导的脓毒症小鼠模型中，我们还观察到血脑屏障破坏、脑部炎症以及认知障碍。在这两种模型中，我们发现内皮细胞中触发受体表达分子-1（TREM - 1）的表达显著增加。内皮细胞特异性敲除TREM - 1可减轻血脑屏障功能障碍和认知障碍。进一步研究表明，TREM - 1会影响参与磷脂酰肌醇3 - 激酶（PI3K）/蛋白激酶B（Akt）信号通路的基因表达。PI3K抑制剂可消除抑制TREM - 1对血脑屏障和认知的保护作用。我们的研究结果表明，内皮细胞TREM - 1通过PI3K/Akt信号通路诱导脓毒症引起的血脑屏障破坏和认知障碍。靶向内皮细胞TREM - 1或PI3K/Akt信号通路可能是维持脓毒症患者血脑屏障完整性和改善认知功能的一种有前景的策略。

REF: Su Y, Zhu W, Su T, et al. Endothelial TREM-1 mediates sepsis-induced blood‒brain barrier disruption and cognitive impairment via the PI3K/Akt pathway. J Neuroinflammation. 2025;22(1):142. Published 2025 May 27. doi:10.1186/s12974-025-03469-5 PMID: 40426195 PMCID: PMC12117814

Effects of M. tuberculosis and HIV-1 infection on in vitro blood-brain barrier function

结核分枝杆菌和HIV - 1感染对体外血脑屏障功能的影响

Tuberculous meningitis is the most severe form of tuberculosis and HIV-1 co-infection worsens the already poor prognosis. However, how Mycobacterium tuberculosis crosses the blood-brain barrier and how HIV-1 influences tuberculous meningitis pathogenesis remains unclear. The results indicate that Mycobacterium tuberculosis can translocate the blood-brain barrier directly to initiate meningitis.

结核性脑膜炎是最严重的结核病类型，人类免疫缺陷病毒 1 型（HIV - 1）合并感染会使本就不佳的预后情况更加恶化。然而，结核分枝杆菌如何穿越血脑屏障以及 HIV - 1 如何影响结核性脑膜炎的发病机制仍不清楚。研究结果表明，结核分枝杆菌可直接穿过血脑屏障引发脑膜炎。

REF: Proust A, Wilkinson KA, Wilkinson RJ. Effects of M. tuberculosis and HIV-1 infection on in vitro blood-brain barrier function. J Neuroinflammation. 2025;22(1):141. Published 2025 May 26. doi:10.1186/s12974-025-03467-7 PMID: 40420159 PMCID: PMC12107840

NLRP3 activation induces BBB disruption and neutrophil infiltration via CXCR2 signaling in the mouse brain

NLRP3激活通过小鼠大脑中的CXCR2信号通路诱导血脑屏障破坏和中性粒细胞浸润

NLRP3 is an intracellular sensor molecule that affects neutrophil functionality and infiltration in brain disorders such as experimental autoimmune encephalomyelitis (EAE). However, the detailed molecular mechanisms underlying the role of NLRP3 in these processes remain unknown. We found that NLRP3 is crucial for neutrophil infiltration, whereas dispensable for neutrophil priming. Notably, NLRP3 activation in neutrophils induced blood-brain barrier (BBB) disruption and neutrophil infiltration into the brain via CXCL1/2 secretion and subsequent activation of the CXCL1/2-CXCR2 signaling axis. Moreover, CXCL1 and CXCL2 in the inflamed brain directly reduced Claudin-5 expression, which regulates BBB permeability in brain endothelial cells. Furthermore, neutrophil-specific NLRP3 activation aggravated EAE pathogenesis by promoting CXCR2-mediated infiltration of both neutrophils and CD4+ T cells into the central nervous system at disease onset. Thus, the CXCL1/2-CXCR2 axis plays a role in EAE progression. Therefore, this chemokine axis could be a potential therapeutic target for attenuating neuroinflammatory diseases through modulating of neutrophil and CD4+ T cell infiltration and BBB disruption.

NLRP3是一种细胞内传感分子，它会影响诸如实验性自身免疫性脑脊髓炎（EAE）等脑部疾病中中性粒细胞的功能和浸润情况。然而，NLRP3在这些过程中发挥作用的详细分子机制仍不清楚。我们发现，NLRP3对中性粒细胞浸润至关重要，但对中性粒细胞的预激作用并非必需。值得注意的是，中性粒细胞中NLRP3的激活可通过分泌CXCL1/2并随后激活CXCL1/2 - CXCR2信号轴，导致血脑屏障（BBB）破坏以及中性粒细胞浸润入脑。此外，炎症脑部的CXCL1和CXCL2可直接降低紧密连接蛋白 - 5的表达，而紧密连接蛋白 - 5可调节脑内皮细胞的血脑屏障通透性。此外，中性粒细胞特异性的NLRP3激活会在疾病发作时促进CXCR2介导的中性粒细胞和CD4+ T细胞浸润入中枢神经系统，从而加重EAE的发病机制。因此，CXCL1/2 - CXCR2轴在EAE进展中发挥作用。所以，通过调节中性粒细胞和CD4+ T细胞浸润以及血脑屏障破坏，这一趋化因子轴可能成为减轻神经炎症性疾病的潜在治疗靶点。

REF: Lee J, Cho W, Yu JW, Hyun YM. NLRP3 activation induces BBB disruption and neutrophil infiltration via CXCR2 signaling in the mouse brain. J Neuroinflammation. 2025;22(1):139. Published 2025 May 24. doi:10.1186/s12974-025-03468-6 PMID: 40413505 PMCID: PMC12102932

Diverse cell types establish a pathogenic immune environment in peripheral neuropathy

多种细胞类型在外周神经病中营造了致病免疫微环境

Neuroinflammation plays a complex and context-dependent role in many neurodegenerative diseases. We identified a key pathogenic function of macrophages in a mouse model of a rare human congenital neuropathy in which SARM1, the central executioner of axon degeneration, is activated by hypomorphic mutations in the axon survival factor NMNAT2. Macrophage depletion blocked and reversed neuropathic phenotypes in this sarmopathy model, revealing SARM1-dependent neuroimmune mechanisms as key drivers of disease pathogenesis. In this study, we investigated the impact of chronic subacute SARM1 activation on the peripheral nerve milieu using single cell/nucleus RNA-sequencing (sc/snRNA-seq). Our analyses reveal an expansion of immune cells (macrophages and T lymphocytes) and repair Schwann cells, as well as significant transcriptional alterations to a wide range of nerve-resident cell types. Notably, endoneurial fibroblasts show increased expression of chemokines (Ccl9, Cxcl5) and complement components (C3, C4b, C6) in response to chronic SARM1 activation, indicating enhanced immune cell recruitment and immune response regulation by non-immune nerve-resident cells. Analysis of CD45+ immune cells in sciatic nerves revealed an expansion of an Il1b+ macrophage subpopulation with increased expression of markers associated with phagocytosis and T cell activation/proliferation. We also found a significant increase in T cells in sarmopathic nerves. Remarkably, T cell depletion rescued motor phenotypes in the sarmopathy model. These findings delineate the significant changes chronic SARM1 activation induces in peripheral nerves and highlights the potential of immunomodulatory therapies for SARM1-dependent peripheral neurodegenerative disease.

神经炎症在许多神经退行性疾病中起着复杂且依赖于具体情境的作用。我们在一种罕见人类先天性神经病的小鼠模型中确定了巨噬细胞的关键致病功能，在该模型中，轴突存活因子NMNAT2的亚效突变激活了轴突退化的核心执行者SARM1。在这种SARM1相关疾病（sarmopathy）模型中，巨噬细胞耗竭阻止并逆转了神经病表型，揭示了SARM1依赖性神经免疫机制是疾病发病机制的关键驱动因素。在本研究中，我们使用单细胞/单细胞核RNA测序（sc/snRNA-seq）研究了慢性亚急性SARM1激活对周围神经微环境的影响。我们的分析显示免疫细胞（巨噬细胞和T淋巴细胞）以及修复性施万细胞数量增加，同时多种神经驻留细胞类型出现显著的转录改变。值得注意的是，神经内膜成纤维细胞在慢性SARM1激活的刺激下，趋化因子（Ccl9、Cxcl5）和补体成分（C3、C4b、C6）表达增加，这表明非免疫性神经驻留细胞增强了免疫细胞招募和免疫反应调节。对坐骨神经中CD45⁺免疫细胞的分析显示，Il1b⁺巨噬细胞亚群数量增加，且与吞噬作用以及T细胞活化/增殖相关的标志物表达增加。我们还发现SARM1相关疾病神经中T细胞显著增多。值得注意的是，耗竭T细胞可挽救SARM1相关疾病模型的运动表型。这些发现描绘了慢性SARM1激活在周围神经中引发的显著变化，并凸显了免疫调节疗法对SARM1依赖性周围神经退行性疾病的潜在应用价值。

REF: Choi J, Strickland A, Loo HQ, et al. Diverse cell types establish a pathogenic immune environment in peripheral neuropathy. J Neuroinflammation. 2025;22(1):138. Published 2025 May 23. doi:10.1186/s12974-025-03459-7 PMID: 40410792 PMCID: PMC12100903

Gut microbiota deficiency reduces neutrophil activation and is protective after ischemic stroke

肠道微生物群缺乏可降低中性粒细胞活化，对缺血性中风具有保护作用

Neutrophils are readily activated immune cells after ischemic stroke in mice and patients. Still, the impact of gut microbiota on neutrophil activation and its influence on inflammatory brain injury remain undefined. We report that natural microbiota colonization of germ-free (GF) mice induces substantial neutrophil activation and deteriorates stroke pathology. The colonized Ex-GF stroke mice had considerably larger infarct sizes and higher sensorimotor deficits than GF littermates. Furthermore, employing an antibiotic-based mouse model of microbiota deficiency, we demonstrate that gut microbiota depletion induces a juvenile neutrophil phenotype characterized by the upregulation of resting state surface receptors, reduced inflammatory proteins, and levels of circulating NETs. This disarming of neutrophil responses was associated with decreased expression of brain inflammatory genes, vascular thrombus formation, reduced infarct size, and alleviated behavioral deficits. We conclude that gut microbes strongly influence neutrophil activation after stroke and thus directly contribute to stroke severity.

在小鼠和患者发生缺血性中风后，中性粒细胞是容易被激活的免疫细胞。不过，肠道微生物群对中性粒细胞激活的影响及其对脑部炎症损伤的作用仍不明确。我们发现，无菌（GF）小鼠经自然微生物群定植后，会引发大量中性粒细胞激活，并加重中风病理状况。与无菌同窝小鼠相比，经微生物群定植的前无菌（Ex - GF）中风小鼠的梗死面积明显更大，感觉运动障碍更严重。此外，我们利用基于抗生素构建的微生物群缺乏小鼠模型，证实肠道微生物群耗竭会诱导出一种幼稚中性粒细胞表型，其特征为静息状态表面受体上调、炎症蛋白减少以及循环中性粒细胞胞外陷阱（NETs）水平降低。这种中性粒细胞反应的“失活”与脑部炎症基因表达降低、血管血栓形成减少、梗死面积缩小以及行为缺陷减轻相关。我们得出结论，肠道微生物在中风后对中性粒细胞激活有显著影响，从而直接影响中风的严重程度。

REF: Tuz AA, Ghosh S, Karsch L, et al. Gut microbiota deficiency reduces neutrophil activation and is protective after ischemic stroke. J Neuroinflammation. 2025;22(1):137. Published 2025 May 23. doi:10.1186/s12974-025-03448-w PMID: 40410847 PMCID: PMC12100894