Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson’s disease

缺氧诱导因子-1α 调节小胶质细胞固有免疫记忆与帕金森病病理

In this study, LPS was used to establish in vitro and in vivo models of innate immune memory. Microglia-specific Hif-1α knockout mice were further employed to elucidate the regulatory role of HIF-1α in innate immune memory and MPTP-induced PD pathology. Our results showed that different paradigms of LPS could induce innate immune training or tolerance in the nigrostriatal pathway of mice. We found that innate immune tolerance lasting for one month protected the dopaminergic system in PD mice, whereas the effect of innate immune training was limited. Deficiency of HIF-1α in microglia impeded the formation of innate immune memory and exerted protective effects in MPTP-intoxicated mice by suppressing neuroinflammation. Therefore, HIF-1α is essential for microglial innate immune memory and can promote neuroinflammation associated with PD.

在这项研究中，LPS用于建立先天免疫记忆的体外和体内模型。小胶质细胞特异性Hif-1α 敲除小鼠进一步用于阐明HIF-1α 在先天免疫记忆和MPTP诱导的PD病理中的调节作用。我们的结果表明，LPS的不同范例可以诱导小鼠黑质纹状体途径的先天免疫训练或耐受。我们发现持续一个月的先天免疫耐受保护了PD小鼠的多巴胺能系统，而先天免疫训练的作用是有限的。小胶质细胞中HIF-1α 的缺乏阻碍了先天免疫记忆的形成，并通过抑制神经炎症在MPTP中毒的小鼠中发挥了保护作用。因此，HIF-1α 对于小胶质细胞先天免疫记忆至关重要，并且可以促进与PD相关的神经炎症。

REF: Dong H, Zhang X, Duan Y, et al. Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson's disease. J Neuroinflammation. 2024;21(1):80. Published 2024 Mar 30. doi:10.1186/s12974-024-03070-2 PMID: 38555419

The immunomodulatory effect of oral NaHCO3 is mediated by the splenic nerve: multivariate impact revealed by artificial neural networks

口服NaHCO3的免疫调节作用是由脾神经介导的: 人工神经网络揭示的多变量影响

We investigated whether oral NaHCO3's immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO3 or water (H2O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO3 led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFα + (M1-like) macrophages, M1-like/M2-like ratio, and SSChigh/SSClow ratio of FSChighCD11bc + cells, decreased in the spleen following NaHCO3 administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO3-induced immunomodulation. Artificial neural networks accurately classified NaHCO3 and H2O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO3-induced immunomodulatory changes to the spleen, emphasizing NaHCO3's potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.

我们研究了口服NaHCO3的免疫调节作用是否由脾神经介导。雌性大鼠接受NaHCO3或水 (H2O) 四天，并使用流式细胞术评估脾脏免疫标志物。NaHCO3导致抗炎标志物，包括cd11bccd206 (M2-like) 巨噬细胞、cd3cd4foxp3细胞 (Tregs) 和Tregs/M1-like比率的显著增加 (p <0.05，和/或部分eta平方> 0.06)。相反，在NaHCO3给药后，脾脏中的促炎标志物，例如cd11bccd38tnf α (M1-like) 巨噬细胞，M1-like/M2-like比和FSChighCD11bc细胞的SSChigh/SSClow比降低。这些作用在脾神经支配的大鼠中被消除，这表明脾神经在介导NaHCO3-induced免疫调节中的必要性。人工神经网络在假手术大鼠中准确分类了NaHCO3和H2O治疗，但在脾神经支配的大鼠中失败了，突出了脾神经的关键作用。此外，脾脏去神经独立地影响treg，M2-like巨噬细胞，treg/M1-like比率和CD11bc CD38细胞，表明手术和治疗的不同效果。主成分分析 (PCA) 进一步支持了单独的效果。我们的发现表明，脾神经将口服NaHCO3-induced的免疫调节变化传递到脾脏，强调了NaHCO3作为IR激活剂的潜力，对广泛的全身性炎症性疾病具有治疗意义。

REF: Alvarez MR, Alkaissi H, Rieger AM, et al. The immunomodulatory effect of oral NaHCO3 is mediated by the splenic nerve: multivariate impact revealed by artificial neural networks. J Neuroinflammation. 2024;21(1):79. Published 2024 Mar 28. doi:10.1186/s12974-024-03067-x PMID: 38549144

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

Tau病变中脂质代谢的变化与神经原纤维病理的进展有关

Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer's disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood. We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. This study revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.

tau的积累导致tau蛋白病 (包括阿尔茨海默病) 中的神经炎症和神经元细胞死亡。随着疾病的进展，脑能量代谢下降。然而，tau蛋白在调节脂质代谢中的作用仍然很少被表征并且知之甚少。我们使用tau蛋白病的转基因大鼠模型来揭示由神经原纤维病理学引起的代谢改变。转基因大鼠表达在N-和C-末端截短的tau片段。对于表型分析，我们基于lc-ms平台对脑组织、CSF和血浆进行了靶向代谢组学和脂质组学分析。为了监测疾病进展，我们采用了来自4、6、8、10、12和14个月大的转基因和对照大鼠的样品。为了研究由病理性tau诱导的脂质组变化中的神经元-神经胶质相互作用，我们使用了完善的多组分细胞模型系统。单变量和多变量统计方法用于数据评估。这项研究表明，在tau病理的不同阶段，脂质代谢受到显着影响。因此，我们的结果表明，病理性tau引起的脂质组成失调会破坏微环境，进一步促进病理学的传播。

REF: Olešová D, Dobešová D, Majerová P, et al. Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies. J Neuroinflammation. 2024;21(1):78. Published 2024 Mar 27. doi:10.1186/s12974-024-03060-4 PMID: 38539208

Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer’s disease

肝特异性脂联素基因治疗抑制小胶质NLRP3-inflammasome活化治疗阿尔茨海默病

The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer's disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated APN gene (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aβ in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aβ-induced IL-1β and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD.

这项研究的重点是开发一种新的，易于处理的治疗方法，用于使用外周APN基因疗法治疗5xfad小鼠的阿尔茨海默氏病 (AD) 相关病理。我们已经产生了表达小鼠突变APN基因 (APNC39S) 的腺相关病毒 (AAV2/8) 并将其转导到仅产生低分子量三聚体APN (APNTri) 的5xfad小鼠的肝脏中。肝脏中单剂量的AAV2/8-APNC39S增加了循环和大脑APN水平，表明过表达的apntrl能够穿过BBB。APNTri的过表达降低了5xfad小鼠大脑中的可溶性和纤维状a β。AAV2/8-APNTri治疗通过抑制小胶质NLRP3-inflammasome活化来减少a β 诱导的IL-1β 和IL-18分泌。在aav-apntri处理的5xfad小鼠中，随着营养不良性神经突的减少，记忆功能显著改善。这些发现表明，过表达三聚体APN的外周基因递送可能是AD的潜在疗法。

REF: Ng RC, Jian M, Ma OK, et al. Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer's disease. J Neuroinflammation. 2024;21(1):77. Published 2024 Mar 27. doi:10.1186/s12974-024-03066-y PMID: 38539253

Single-cell RNA sequencing reveals the immune features and viral tropism in the central nervous system of mice infected with Japanese encephalitis virus

单细胞RNA测序揭示感染日本脑炎病毒小鼠中枢神经系统的免疫特征和病毒嗜性

Despite extensive research on JEV pathogenesis, the effect of JEV on the cellular composition and viral tropism towards distinct neuronal subtypes in the brain is still not well comprehended. To address these issues, we performed single-cell RNA sequencing (scRNA-seq) on cells isolated from the JEV-highly infected regions of mouse brain. We obtained 88,000 single cells and identified 34 clusters representing 10 major cell types. The scRNA-seq results revealed an increasing amount of activated microglia cells and infiltrating immune cells, including monocytes & macrophages, T cells, and natural killer cells, which were associated with the severity of symptoms. Additionally, we observed enhanced communication between individual cells and significant ligand-receptor pairs related to tight junctions, chemokines and antigen-presenting molecules upon JEV infection, suggesting an upregulation of endothelial permeability, inflammation and antiviral response. Moreover, we identified that Baiap2-positive neurons were highly susceptible to JEV. Our findings provide valuable clues for understanding the mechanism of JEV induced neuro-damage and inflammation as well as developing therapies for Japanese encephalitis.

尽管对JEV发病机制进行了广泛的研究，但JEV对大脑中不同神经元亚型的细胞组成和病毒嗜性的影响仍未得到很好的理解。为了解决这些问题，我们对从小鼠大脑的JEV高度感染区域分离的细胞进行了单细胞RNA测序 (scrna-seq)。我们获得了88,000个单细胞，并鉴定了代表10种主要细胞类型的34个簇。Scrna-seq结果显示，激活的小胶质细胞和浸润性免疫细胞的数量增加，包括单核细胞和巨噬细胞，T细胞和自然杀伤细胞，与症状的严重程度相关。此外，我们观察到JEV感染后单个细胞与紧密连接，趋化因子和抗原呈递分子相关的重要配体-受体对之间的通讯增强，表明内皮通透性，炎症和抗病毒反应上调。此外，我们发现Baiap2-positive神经元对JEV高度敏感。我们的发现为理解JEV诱导的神经损伤和炎症的机制以及开发日本脑炎的疗法提供了有价值的线索。

REF: Yang L, Xiong J, Liu Y, et al. Single-cell RNA sequencing reveals the immune features and viral tropism in the central nervous system of mice infected with Japanese encephalitis virus. J Neuroinflammation. 2024;21(1):76. Published 2024 Mar 26. doi:10.1186/s12974-024-03071-1 PMID: 38532383

Wnt5a/β-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration

Wnt5a/β-catenin介导的上皮-间质转化: 新生血管性年龄相关性黄斑变性视网膜下纤维化的关键驱动因素

In this study, we aim to investigate the underlying mechanisms involved in the Wnt signaling during the EMT of RPE cells and in the pathological process of subretinal fibrosis secondary to nAMD. In vivo, the induction of subretinal fibrosis was performed in male C57BL/6J mice through laser photocoagulation. Either FH535 (a β-catenin inhibitor) or Box5 (a Wnt5a inhibitor) was intravitreally administered on the same day or 14 days following laser induction. The RPE-Bruch's membrane-choriocapillaris complex (RBCC) tissues were collected and subjected to Western blot analysis and immunofluorescence to examine fibrovascular and Wnt-related markers. In vitro, transforming growth factor beta 1 (TGFβ1)-treated ARPE-19 cells were co-incubated with or without FH535, Foxy-5 (a Wnt5a-mimicking peptide), Box5, or Wnt5a shRNA, respectively. The changes in EMT- and Wnt-related signaling molecules, as well as cell functions were assessed using qRT-PCR, nuclear-cytoplasmic fractionation assay, Western blot, immunofluorescence, scratch assay or transwell migration assay. The cell viability of ARPE-19 cells was determined using Cell Counting Kit (CCK)-8. Our study reveals a reciprocal activation between Wnt5a and β-catenin to mediate EMT as a pivotal driver of subretinal fibrosis in nAMD. This positive feedback loop provides valuable insights into potential therapeutic strategies to treat subretinal fibrosis in nAMD patients.

在这项研究中，我们旨在研究RPE细胞EMT过程中Wnt信号转导以及nAMD继发视网膜下纤维化的病理过程中涉及的潜在机制。在体内，通过激光光凝在雄性C57BL/6J小鼠中进行视网膜下纤维化的诱导。在激光诱导后的同一天或14天，玻璃体内施用FH535 (β-连环蛋白抑制剂) 或Box5 (Wnt5a抑制剂)。收集rpe-bruch膜-脉络膜毛细血管复合物 (RBCC) 组织，并进行蛋白质印迹分析和免疫荧光以检查纤维血管和Wnt相关标志物。在体外，将转化生长因子 β1 (TGFβ1) 处理的ARPE-19细胞分别与或不与FH535，Foxy-5 (Wnt5a-mimicking肽)，Box5或Wnt5a shRNA共同孵育。使用qrt-pcr、核-细胞质分级测定、蛋白质印迹、免疫荧光、划痕测定或transwell迁移测定评估EMT和Wnt相关信号分子的变化以及细胞功能。使用细胞计数试剂盒 (CCK)-8测定ARPE-19细胞的细胞活力。我们的研究揭示了Wnt5a和 β-catenin之间的相互激活，介导EMT是nAMD视网膜下纤维化的关键驱动因素。这种积极的反馈回路为治疗nAMD患者视网膜下纤维化的潜在治疗策略提供了有价值的见解。

REF: Liu D, Du J, Xie H, et al. Wnt5a/β-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration. J Neuroinflammation. 2024;21(1):75. Published 2024 Mar 26. doi:10.1186/s12974-024-03068-w PMID: 38532410

The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment

小鼠视网膜色素上皮在视网膜脱离后产生先天免疫防御反应

Retinal detachment (RD) causes separation of the neurosensory retina from the underlying RPE, disrupting the functional and metabolic relationships between these layers. Although the retinal response to RD is highly studied, little is known about how the RPE responds to loss of this interaction. RNA sequencing (RNA-Seq) was used to compare normal and detached RPE in the C57BL6/J mouse. The naïve mouse RPE transcriptome was compared to previously published RPE signature gene lists and from the union of these 14 genes (Bmp4, Crim1, Degs1, Gja1, Itgav, Mfap3l, Pdpn, Ptgds, Rbp1, Rnf13, Rpe65, Slc4a2, Sulf1 and Ttr) representing a core signature gene set applicable across rodent and human RPE was derived. Gene ontology enrichment analysis (GOEA) of the mouse RPE transcriptome identified expected RPE features and functions, such as pigmentation, phagocytosis, lysosomal and proteasomal degradation of proteins, and barrier function. Differentially expressed genes (DEG) at 1 and 7 days post retinal detachment (dprd) were defined as mRNA with a significant (padj≤0.05) fold change (FC) of 0.67 ≥ FC ≥ 1.5 in detached versus naïve RPE. The RPE transcriptome exhibited dramatic changes at 1 dprd, with 2297 DEG identified. The KEGG pathways and biological process GO groups related to innate immune responses were significantly enriched. Lipocalin 2 (Lcn2) and several chemokines were upregulated, while numerous genes related to RPE functions, such as pigment synthesis, visual cycle, phagocytosis, and tight junctions were downregulated at 1 dprd. The response was largely transient, with only 18 significant DEG identified at 7 dprd, including upregulation of complement gene C4b. Validation studies confirmed RNA-Seq results. Thus, the RPE quickly downregulates cell-specific functions and mounts an innate immune defense response following RD. Our data demonstrate that the RPE contributes to the inflammatory response to RD and may play a role in attraction of immune cells to the subretinal space.

视网膜脱离 (RD) 导致神经感觉视网膜与下面的RPE分离，破坏了这些层之间的功能和代谢关系。尽管对RD的视网膜反应进行了深入研究，但对RPE如何响应这种相互作用的丧失知之甚少。使用RNA测序 (rna-seq) 比较C57BL6/J小鼠中的正常和脱离的RPE。将幼稚小鼠RPE转录组与先前发表的RPE签名基因列表以及这14个基因 (Bmp4，Crim1，Degs1，Gja1，Itgav，Mfap3l，Pdpn，Ptgds，Rbp1，Rnf13，Rpe65，Slc4a2，Sulf1和Ttr) 的联合进行比较衍生出代表适用于啮齿动物和人RPE的核心签名基因集。小鼠RPE转录组的基因本体论富集分析 (GOEA) 确定了预期的RPE特征和功能，例如色素沉着，吞噬作用，蛋白质的溶酶体和蛋白酶体降解以及屏障功能。视网膜脱离 (dprd) 后1天和7天的差异表达基因 (DEG) 定义为mRNA，在脱离与未脱离的RPE中具有0.67 ≥ FC ≥ 1.5的显着 (padj ≤ 0.05) 倍数变化 (FC)。RPE转录组在1 dprd时显示出显着变化，鉴定出2297 DEG。与先天免疫应答相关的KEGG途径和生物过程GO组显著富集。脂质运载蛋白2 (Lcn2) 和几种趋化因子上调，而与RPE功能相关的许多基因，如色素合成、视觉周期、吞噬作用和紧密连接在1 dprd下调。反应在很大程度上是短暂的，在7 dprd处仅鉴定出18个显着的DEG，包括补体基因C4b的上调。验证研究证实了rna-seq结果。因此，RPE快速下调细胞特异性功能，并在RD后产生先天免疫防御反应。我们的数据表明，RPE有助于对RD的炎症反应，并可能在吸引免疫细胞到视网膜下腔中发挥作用。

REF: Abcouwer SF, Miglioranza Scavuzzi B, Kish PE, et al. The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment. J Neuroinflammation. 2024;21(1):74. Published 2024 Mar 25. doi:10.1186/s12974-024-03062-2 PMID: 38528525

P2X7 receptor antagonists modulate experimental autoimmune neuritis via regulation of NLRP3 inflammasome activation and Th17 and Th1 cell differentiation

P2X7受体拮抗剂通过调节NLRP3炎性体激活和Th17和Th1细胞分化调节实验性自身免疫性神经炎

In this study, we initially assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4+ T cells, CD8+ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0180 - 199 peptide. We analyzed CD4+ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4+ T cells in rats with EAN.Suppression of P2X7R relieved EAN manifestation by regulating CD4+ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

在这项研究中，我们最初使用流式细胞术和qrt-pcr评估了GBS患者外周血中嘌呤能P2X7R的表达。接下来，我们使用免疫荧光标记和流式细胞术研究了大鼠坐骨神经和脾脏内CD4 T细胞，CD8 T细胞和巨噬细胞中P2 X7R的表达。P2X7R拮抗剂亮蓝G (BBG) 用于检查其对由P0180-199肽预防接种诱导的实验性自身免疫性神经炎 (EAN) 大鼠的治疗作用。我们使用流式细胞术分析了脾脏单个核细胞中CD4 T细胞的分化，通过免疫荧光染色评估了坐骨神经中Th17细胞的分化，并使用rt-pcr检查了促炎细胞因子mRNA的表达。此外，我们进行蛋白质印迹以评估坐骨神经内P2X7R和NLRP3-related炎性蛋白的表达。最后，我们利用流式细胞术和免疫荧光标记技术检测了EAN大鼠CD4 T细胞上NLRP3的表达。P2X7R的抑制通过调节CD4 T细胞分化和NLRP3炎性体激活来缓解EAN的表现。这一发现强调了P2X7R作为抗炎治疗靶点的潜在意义，推进了GBS的研究和管理。

REF: Xie Y, Han R, Li Y, et al. P2X7 receptor antagonists modulate experimental autoimmune neuritis via regulation of NLRP3 inflammasome activation and Th17 and Th1 cell differentiation. J Neuroinflammation. 2024;21(1):73. Published 2024 Mar 25. doi:10.1186/s12974-024-03057-z PMID: 38528529

Inflammation-induced TRPV4 channels exacerbate blood–brain barrier dysfunction in multiple sclerosis

炎症诱导的TRPV4通道加重多发性硬化患者血脑屏障功能障碍

In human post-mortem MS brain tissue, we observed a region-specific increase in endothelial TRPV4 expression around mixed active/inactive lesions, which coincided with perivascular microglia enrichment in the same area. Using in vitro models, we identified that microglia-derived tumor necrosis factor-α (TNFα) induced brain endothelial TRPV4 expression. Also, we found that TRPV4 levels influenced brain endothelial barrier formation via expression of the brain endothelial tight junction molecule claudin-5. In contrast, during an inflammatory insult, TRPV4 promoted a pathological endothelial molecular signature, as evidenced by enhanced expression of inflammatory mediators and cell adhesion molecules. Moreover, TRPV4 activity mediated T cell extravasation across the brain endothelium. Collectively, this study suggests a novel role for endothelial TRPV4 in MS, in which enhanced expression contributes to MS pathogenesis by driving BBB dysfunction and immune cell migration.

在人类死后MS脑组织中，我们观察到混合的活性/非活性病变周围内皮TRPV4表达的区域特异性增加，这与同一区域的血管周围小胶质细胞富集相吻合。使用体外模型，我们确定了小胶质细胞衍生的肿瘤坏死因子-α (tnf α) 诱导脑内皮TRPV4表达。此外，我们发现TRPV4水平通过脑内皮紧密连接分子claudin-5的表达影响脑内皮屏障的形成。相反，在炎症损伤期间，TRPV4促进了病理性内皮分子签名，如炎症介质和细胞粘附分子的表达增强所证明的。此外，TRPV4活性介导T细胞穿过脑内皮的外渗。总的来说，这项研究表明内皮TRPV4在MS中的新作用，其中增强的表达通过驱动BBB功能障碍和免疫细胞迁移而有助于MS发病。

REF: Hansen CE, Kamermans A, Mol K, et al. Inflammation-induced TRPV4 channels exacerbate blood-brain barrier dysfunction in multiple sclerosis. J Neuroinflammation. 2024;21(1):72. Published 2024 Mar 23. doi:10.1186/s12974-024-03069-9 PMID: 38521959