Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease

前颗粒蛋白和GPNMB：神经退行性疾病中内溶酶体功能和炎症的相互作用

Alterations in progranulin (PGRN) expression are associated with multiple neurodegenerative diseases (NDs), including frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and lysosomal storage disorders (LSDs). Recently, the loss of PGRN was shown to result in endo-lysosomal system dysfunction and an age-dependent increase in the expression of another protein associated with NDs, glycoprotein non-metastatic B (GPNMB). PGRN and GPNMB are interrelated proteins that regulate disease-relevant processes and may have value as therapeutic targets to delay disease progression or extend therapeutic windows.

原颗粒蛋白(PGRN)表达的改变与多种神经退行性疾病(NDS)相关，包括额颞叶痴呆(FTD)、阿尔茨海默病(AD)、帕金森病(PD)和溶酶体储存障碍(LSD)。近来研究发现，PGRN的缺失可导致内源性溶酶体系统功能障碍以及与NDS相关的另一种蛋白--糖蛋白非转移性B(GPNMB)的表达随年龄增加而增加。PGRN和GPNMB是相互关联的蛋白质，调节与疾病相关的过程，可能作为治疗靶点来延缓疾病进展或延长治疗窗口。

REF: Gillett DA, Wallings RL, Uriarte Huarte O, Tansey MG. Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease. J Neuroinflammation. 2023;20(1):286. Published 2023 Nov 30. doi:10.1186/s12974-023-02965-w PMID: 38037070 PMCID: PMC10688479

Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells

单细胞测序揭示LRG1‘S通过调节多种细胞在脑缺血再灌注损伤中的作用

Cerebral ischemia‒reperfusion injury causes significant harm to human health and is a major contributor to stroke-related deaths worldwide. Current treatments are limited, and new, more effective prevention and treatment strategies that target multiple cell components are urgently needed. Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia‒reperfusion injury, but the exact mechanism of it is unknown. Our results has shown that Lrg1 mediates numerous pathological processes involved in cerebral ischemia‒reperfusion injury by altering the functional states of various cell types, thereby rendering it a promising therapeutic target for cerebral ischemia‒reperfusion injury.

脑缺血再灌注损伤对人类健康造成严重危害，是全球范围内脑卒中相关死亡的主要原因。目前的治疗方法有限，迫切需要针对多种细胞成分的新的、更有效的预防和治疗策略。富含亮氨酸的α 2糖蛋白1（Leucine-rich alpha-2 glycoprotein 1，Lrg 1）与脑缺血再灌注损伤的进展有关，但其确切机制尚不清楚。 我们的研究结果表明，Lrg 1介导的许多病理过程中涉及脑缺血再灌注损伤，通过改变各种类型的细胞的功能状态，从而使其成为一个有前途的治疗脑缺血再灌注损伤的目标。

REF: Ruan Z, Cao G, Qian Y, et al. Single-cell RNA sequencing unveils Lrg1's role in cerebral ischemia‒reperfusion injury by modulating various cells. J Neuroinflammation. 2023;20(1):285. Published 2023 Nov 30. doi:10.1186/s12974-023-02941-4 PMID: 38037097 PMCID: PMC10687904

TRIM45 aggravates microglia pyroptosis via Atg5/NLRP3 axis in septic encephalopathy

TRIM45通过ATG5/NLRP3轴加重感染性脑病小胶质细胞下垂

Neuroinflammation mediated by microglial pyroptosis is an important pathogenic mechanism of septic encephalopathy (SAE). It has been reported that TRIM45 is associated with tumours and inflammatory diseases. However, the role of TRIM45 in SAE and the relationship between TRIM45 and microglial pyroptosis are unknown. In this study, we found that TRIM45 played an important role in regulating microglial pyroptosis and the molecular mechanism. TRIM45 plays a key role in neuroinflammation caused by LPS, and the mechanism may involve TRIM45-mediated exacerbation of microglial pyroptosis via the Atg5/NLRP3 axis.

小胶质细胞下垂介导的神经炎症是感染性脑病(SAE)的重要发病机制。据报道，TRIM45与肿瘤和炎症性疾病有关。然而，TRIM45在SAE中的作用以及TRIM45与小胶质细胞下垂的关系尚不清楚。在本研究中，我们发现TRIM45在小胶质细胞下垂的调控中起着重要的作用，并探讨了其分子机制。TRIM45在脂多糖引起的神经炎症中起关键作用，其机制可能与TRIM45通过ATG5/NLRP3轴加重小胶质细胞下垂有关。

REF: Huang X, Ye C, Zhao X, et al. TRIM45 aggravates microglia pyroptosis via Atg5/NLRP3 axis in septic encephalopathy. J Neuroinflammation. 2023;20(1):284. Published 2023 Nov 30. doi:10.1186/s12974-023-02959-8 PMID: 38037161 PMCID: PMC10688018

Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis

神经炎症、记忆和抑郁：海马神经发生的新途径

As one of most common and severe mental disorders, major depressive disorder (MDD) significantly increases the risks of premature death and other medical conditions for patients. Neuroinflammation is the abnormal immune response in the brain, and its correlation with MDD is receiving increasing attention. Neuroinflammation has been reported to be involved in MDD through distinct neurobiological mechanisms, among which the dysregulation of neurogenesis in the dentate gyrus (DG) of the hippocampus (HPC) is receiving increasing attention. The DG of the hippocampus is one of two niches for neurogenesis in the adult mammalian brain, and neurotrophic factors are fundamental regulators of this neurogenesis process. The reported cell types involved in mediating neuroinflammation include microglia, astrocytes, oligodendrocytes, meningeal leukocytes, and peripheral immune cells which selectively penetrate the blood-brain barrier and infiltrate into inflammatory regions. This review summarizes the functions of the hippocampus affected by neuroinflammation during MDD progression and the corresponding influences on the memory of MDD patients and model animals.

作为最常见和最严重的精神障碍之一，严重抑郁障碍(MDD)显著增加了患者过早死亡和其他疾病的风险。神经炎症是脑内的一种异常免疫反应，与MDD的相关性日益受到重视。神经炎症通过不同的神经生物学机制参与了MDD的发病，其中海马齿状回(DG)神经发生的失调越来越受到关注。海马齿状回是成年哺乳动物脑内神经发生的两个区位之一，神经营养因子是这一神经发生过程的基本调节因子。已报道的参与神经炎症的细胞类型包括小胶质细胞、星形胶质细胞、少突胶质细胞、脑膜白细胞和外周免疫细胞，它们选择性地穿透血脑屏障并渗透到炎症区。本文综述了神经炎症在MDD进展过程中对海马区功能的影响，以及对MDD患者和模型动物记忆的影响。

REF: Wu A, Zhang J. Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis. J Neuroinflammation. 2023;20(1):283. Published 2023 Nov 27. doi:10.1186/s12974-023-02964-x PMID: 38012702 PMCID: PMC10683283

Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer’s disease mouse model

抑制微折叠细胞通过调节小胶质细胞功能改善阿尔茨海默病小鼠模型的早期病理表型

The gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer's disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown. Five familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age. Our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications.

肠道微生物区系作为阿尔茨海默病(AD)的致病因素最近引起了人们的注意。微折叠(M)细胞在肠道对外界抗原的免疫反应中发挥关键作用，也被用于病原体和蛋白质进入体内。然而，M细胞的变化是否会影响肠道环境，从而改变阿尔茨海默病的脑部病理仍不清楚。用5只家族性AD(5xFAD)和5xFAD来源的粪便微生物移植(5xFAD-FMT)幼龄小鼠观察AD环境中M细胞的变化。接下来，为了确定M细胞缺失对AD环境的影响，培育了5xFAD小鼠和SPIB基因敲除小鼠，并在6个月或9个月龄时进行了行为学和组织学分析。我们的发现提供了抑制M细胞可以阻止AD进展的证据，具有治疗意义。

REF: Kim N, Ju IG, Jeon SH, et al. Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer's disease mouse model. J Neuroinflammation. 2023;20(1):282. Published 2023 Nov 27. doi:10.1186/s12974-023-02966-9 PMID: 38012646 PMCID: PMC10680211

OTUD1 ameliorates cerebral ischemic injury through inhibiting inflammation by disrupting K63-linked deubiquitination of RIP2

OTUD 1通过破坏RIP2的K63连接的去泛素化抑制炎症来改善脑缺血损伤

Inflammatory response triggered by innate immunity plays a pivotal element in the progress of ischemic stroke. Receptor-interacting kinase 2 (RIP2) is implicated in maintaining immunity homeostasis and regulating inflammatory response. However, the underlying mechanism of RIP2 in ischemic stroke is still not well understood. Hence, the study investigated the role and the ubiquitination regulatory mechanism of RIP2 in ischemic stroke. The findings suggested that RIP2 mediated cerebral ischemic lesion via stimulating inflammatory response, and OTUD1 ameliorated brain injury after ischemia through inhibiting RIP2-induced NF-κB activation by specifically cleaving K63-linked ubiquitination of RIP2.

先天免疫引发的炎症反应在缺血性卒中的发病过程中起着关键作用。受体相互作用蛋白2(RIP2)参与维持免疫平衡和调节炎症反应。然而，RIP2在缺血性卒中中的潜在机制仍不清楚。因此，本研究探讨了RIP2在缺血性卒中中的作用及其泛素化调节机制。结果提示，RIP2通过刺激炎症反应介导脑缺血损伤，而OTUD1OTUD1通过特异性切割K63连接的RIP2泛素化抑制RIP2诱导的NF-κB活化，从而减轻脑缺血后的损伤。

REF: Zheng S, Li Y, Song X, et al. OTUD1 ameliorates cerebral ischemic injury through inhibiting inflammation by disrupting K63-linked deubiquitination of RIP2. J Neuroinflammation. 2023;20(1):281. Published 2023 Nov 27. doi:10.1186/s12974-023-02968-7 PMID: 38012669 PMCID: PMC10680203

Hypothermia combined with extracellular vesicles from clonally expanded immortalized mesenchymal stromal cells improves neurodevelopmental impairment in neonatal hypoxic-ischemic brain injury

低温联合克隆扩增的永生化间充质干细胞胞外囊泡改善新生儿缺氧缺血性脑损伤的神经发育障碍

Neonatal encephalopathy following hypoxia-ischemia (HI) is a leading cause of childhood death and morbidity. Hypothermia (HT), the only available but obligatory therapy is limited due to a short therapeutic window and limited efficacy. An adjuvant therapy overcoming limitations of HT is still missing. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have shown promising therapeutic effects in various brain injury models. Challenges associated with MSCs' heterogeneity and senescence can be mitigated by the use of EVs from clonally expanded immortalized MSCs (ciMSCs). In the present study, we hypothesized that intranasal ciMSC-EV delivery overcomes limitations of HT. Intranasal delivery of ciMSC-EVs represents a novel adjunct therapy, overcoming limitations of acute HT thereby offering new possibilities for improving long-term outcomes in neonates with HI-induced brain injury.

新生儿缺氧缺血脑病是导致儿童死亡和发病的主要原因。低温治疗是目前唯一可用的强制性治疗方法，但由于治疗时间短、疗效有限而受到限制。一种克服HT局限性的辅助疗法仍然缺乏。间充质基质细胞(MSC)来源的细胞外小泡(EVS)在各种脑损伤模型中显示出良好的治疗效果。克隆扩增的永生间充质干细胞(CiMSCs)的EVS的使用可以缓解与MSCs的异质性和衰老相关的挑战。在本研究中，我们假设经鼻腔给药克服了羟色胺的局限性。鼻腔给药代表了一种新的辅助治疗方法，克服了急性羟色胺的局限性，从而为改善缺氧缺血性脑损伤新生儿的长期预后提供了新的可能性。

REF: Labusek N, Ghari P, Mouloud Y, et al. Hypothermia combined with extracellular vesicles from clonally expanded immortalized mesenchymal stromal cells improves neurodevelopmental impairment in neonatal hypoxic-ischemic brain injury. J Neuroinflammation. 2023;20(1):280. Published 2023 Nov 27. doi:10.1186/s12974-023-02961-0 PMID: 38012640 PMCID: PMC10680187

Protective role of IL-17-producing γδ T cells in a laser-induced choroidal neovascularization mouse model

产生IL-17的γδT细胞对激光诱导的小鼠脉络膜新生血管的保护作用

Vision loss in patients with wet/exudative age-related macular degeneration (AMD) is associated with choroidal neovascularization (CNV), and AMD is the leading cause of irreversible vision impairment in older adults. Interleukin-17A (IL-17A) is a component of the microenvironment associated with some autoimmune diseases. Previous studies have indicated that wet AMD patients have elevated serum IL-17A levels. However, the effect of IL-17A on AMD progression needs to be better understood. We aimed to investigate the role of IL-17A in a laser-induced CNV mouse model. Our findings provide new insight into the protective effect of IL-17A in a laser-induced CNV model and reveal a novel regulatory role of IL-17A-producing γδ T cells in the ocular microenvironment in wet AMD.

湿性/渗出型老年性黄斑变性(AMD)患者的视力丧失与脉络膜新生血管(CNV)有关，AMD是老年人不可逆性视力障碍的主要原因。白介素17A(IL-17A)是与某些自身免疫性疾病相关的微环境的组成部分。以往的研究表明，湿性AMD患者血清IL-17A水平升高。然而，需要更好地了解IL-17A在AMD进展中的作用。本研究旨在探讨IL-17A在激光诱导CNV小鼠模型中的作用。我们的发现为IL-17A在激光诱导的新生血管模型中的保护作用提供了新的见解，并揭示了产生IL-17A的γδT细胞在湿性AMD眼部微环境中的新的调节作用。

REF: Chang YH, Hsing CH, Chiu CJ, Wu YR, Hsu SM, Hsu YH. Protective role of IL-17-producing γδ T cells in a laser-induced choroidal neovascularization mouse model. J Neuroinflammation. 2023;20(1):279. Published 2023 Nov 25. doi:10.1186/s12974-023-02952-1 PMID: 38007487 PMCID: PMC10676594

14-3-3 \(\upzeta /\updelta\)-reported early synaptic injury in Alzheimer’s disease is independently mediated by sTREM2

14-3-3 \（\upzeta /\updelta\）报道的阿尔茨海默病早期突触损伤独立由sTREM 2介导

Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.

突触丢失与阿尔茨海默病（AD）后期的tau聚集和小胶质细胞活化密切相关。然而，突触损伤发生在AD的早期，在tau积累的非常早期阶段。目前还不清楚小胶质细胞激活是否独立地导致突触分裂之前，tau蛋白聚集出现。我们的研究结果表明，sTREM2在tau积累的早期阶段介导突触损伤，强调了小胶质细胞活化对AD疾病传播的重要性。

REF: Woo MS, Nilsson J, Therriault J, et al. 14-3-3 [Formula: see text]-reported early synaptic injury in Alzheimer's disease is independently mediated by sTREM2. J Neuroinflammation. 2023;20(1):278. Published 2023 Nov 24. doi:10.1186/s12974-023-02962-z PMID: 38001539 PMCID: PMC10675887