缺血性卒中后小胶质细胞介导的炎性信号通路

小胶质细胞是中枢神经系统最主要的免疫细胞,在介导中枢神经系统免疫应答中起着关键作用.在缺血性卒中后的病理学过程中,无菌性炎症是关键因素.通过损伤相关配体与相应受体结合,小胶质细胞激活并诱导一系列炎性信号.文章从Toll样受体、炎性小体、细胞因子受体、Notch信号以及其他信号通路介绍缺血性卒中后小胶质细胞的激活和炎性反应.     

Toll 样受体4与脑缺血再灌注损伤的关系研究进展

Toll样受体4(TLR4)是先天性免疫系统的一种跨膜受体蛋白,属于Ⅰ型跨膜糖蛋白受体,可以识别外源性病原相关分子模式和内源性损伤相关分子模式,并启动免疫应答。在脑缺血再灌注过程中,小胶质细胞、星形胶质细胞及损伤的神经元等产生并释放大量的低分子透明质酸、热休克蛋白等物质,作为内源性配体激活TLR4介导的信号通路,产生炎性级联反应,在脑缺血再灌注损伤的发生、发展过程中发挥关键作用。     

小胶质细胞Toll样受体2与脑缺血

急性脑缺血后,小胶质细胞被迅速激活,发挥神经修复和神经毒性的双刃剑作用.近年来的研究表明,小胶质细胞的这种双重作用可通过Toll样受体2（Toll-like receptor 2,TLR2）信号转导通路来实现.因此,合理调控小胶质细胞TLR2表达有可能在一定程度上提高对脑缺血的干预效果.文章对TLR2在脑缺血中的作用机制以及可能的干预措施进行了综述.     

TLR4介导小鼠小胶质细胞自噬在脑出血后炎症反应的作用机制研究

目的研究TLR4介导小胶质细胞自噬在脑出血后炎症反应的作用机制。方法从C57BL/6J小鼠中提取分离原代小胶质细胞,分组1中,A组:小胶质细胞;B组:小胶质细胞+阴性siRNA转染;应用C组:小胶质细胞+TLR4-siRNA转染。应用Q-PCR和Western Blot检测分组1中TLR4的表达。分组2中,D组:小胶质细胞+等量的对照溶剂(0.9%NaCl);E组:小胶质细胞+自噬抑制剂(3-MA);F组:小胶质细胞+control-siRNA+3-MA;G组:小胶质细胞+TLR4-siRNA+等量的对照溶剂(0.9%NaCl);H组:小胶质细胞+TLR4-siRNA+3-MA。Western Blot检测LC3-Ⅱ/Ⅰ比值、TLR4、MyD88和核转录因子(NF-κB)蛋白表达。ELISA检测细胞因子肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)水平。结果 (1)A组和B组TLR4 mRNA和蛋白表达水平无明显变化(P>0.05);与B组相比,C组TLR4 mRNA和蛋白表达水平下调(P <0.05)。(2)D组、E组和F组TLR4、MyD88和NF-κB p65蛋白水平无明显变化(P>0.05);与D组相比,G组TLR4、MyD88和NF-κB p65蛋白水平下调(P <0.05);与F组相比,H组TLR4、MyD88和NF-κB p65蛋白水平下调(P <0.05)。E组和F组LC3-Ⅱ/Ⅰ比值、TNF-α、IL-1β、IL-6水平无明显变化(P>0.05);与F组相比,H组LC3-Ⅱ/Ⅰ比值、TNF-α、IL-1β、IL-6水平下降(P <0.05);与G组相比,H组LC3-Ⅱ/Ⅰ比值、TNF-α、IL-1β、IL-6水平下降(P <0.05)。结论 TLR4-siRNA可抑制TLR4介导的小胶质细胞自噬,从而减轻自噬引起的脑出血炎症损伤。     

N-乙酰半胱氨酸对高糖合并缺血缺氧小胶质细胞中Toll样受体4通路的作用研究

目的研究N-乙酰半胱氨酸(NAC)对高糖合并缺血缺氧小胶质细胞中Toll样受体4(TLR4)通路的作用。方法体外培养小胶质细胞,分为7组:正常组、对照组、高糖组、模型组、NAC组、NAC高糖组和NAC模型组(后3组加NAC 1mmol/L干预),分别在不同的培养液、正常培养箱或缺氧培养箱培养12h建立体外细胞模型。采用TUNEL染色观察小胶质细胞凋亡的病理变化,采用RT-PCR检测各组细胞TLR4通路中TLR4、髓样分化因子88(MyD88)、NF-κB、白细胞介素1β(IL-1β)mRNA表达水平。结果对照组、高糖组和模型组较正常组小胶质细胞凋亡率显著升高(0.36±0.03、0.33±0.02、0.37±0.02 vs 0.15±0.02,P0.05),NAC组、NAC高糖组和NAC模型组较对照组、高糖组和模型组小胶质细胞凋亡率显著下降(0.20±0.02 vs 0.36±0.03,0.21±0.02 vs 0.33±0.02,0.22±0.02 vs 0.37±0.02,P0.05),仅高糖组与NAC高糖组MyD88无明显差异(P0.05),NAC组、NAC高糖组和NAC模型组TLR4,MyD88,NF-κB,IL-1βmRNA表达较对照组、高糖组和模型组明显降低(P0.05)。结论NAC可以减轻高糖及缺血缺氧对小胶质细胞的损伤,其机制可能与抑制TLR4炎症相关通路有关。     

胶质微环境与中枢神经系统损伤修复

中枢神经系统(central mervous system,CNS)损伤包括腩损伤和脊髓损伤,致残率和病死率较高.因此,CNS损伤修复一直是神经科学领域的一个研究重点和热点.成年哺乳动物神经元的内在再生能力有限是CNS损伤后再生困难的原因之一,但更为重要的原因是损伤局部抑制性胶质微环境的形成.文章就胶质微环境内星形胶质细胞、小胶质细胞、少突胶质细胞等各类组成细胞在CNS损伤修复中的作用做了综述.     

TREM2对小胶质细胞的免疫调控在缺血性卒中中的作用

缺血性卒中是一种常见的神经系统疾病, 可导致神经元死亡和神经功能障碍。小胶质细胞是中枢神经系统的主要免疫细胞, 参与卒中后炎症和组织修复。髓样细胞表达的触发受体2(triggering receptor expressed on myeloid cells 2, TREM2)是一种在小胶质细胞表面表达的受体, 在缺血性卒中后神经元存活和神经修复方面发挥着多方面的作用, 包括促进小胶质细胞的吞噬作用、抑制过度的炎症反应、维持小胶质细胞的增殖和存活、保护神经元免受损伤以及促进神经功能恢复。因此, 阐明脑缺血后TREM2对小胶质细胞的免疫调节机制, 对于探索缺血性卒中新的治疗方向具有重要意义。     

小胶质细胞在病毒性中枢神经系统感染中的作用

小胶质细胞是中枢神经系统中的免疫细胞,是中枢神经系统抵抗病原体入侵的第一道防线。当病原微生物进入脑组织后,小胶质细胞迅速做出反应,识别、吞噬病原微生物,呈递抗原和分泌多种生物活性物质。但是,小胶质细胞的过度活化又可诱发中枢神经系统免疫病理损伤或神经退行性病变。因而,具有生理和病理双重作用。本文就小胶质细胞在病毒感染性中枢神经系统疾病中的作用及其机制进行综述。     

右美托咪啶对脑缺血再灌注损伤大鼠的影响

目的 探讨α2-肾上腺素受体激动剂右美托咪啶(Precedex)对脑缺血再灌注模型大鼠的影响。方法 构建脑缺血再灌注损伤模型鼠，并使用Precedex进行干预。检测评估神经功能、脑含水量、梗死面积及小胶质细胞中的分子蛋白表达，从而进行Precedex药物的效应判断。结果 Precedex药物有效降低Toll样受体(TLR)4和核转录因子(NF)-κB p65的mRNA和蛋白的表达量(P<0.05),显著抑制炎症因子肿瘤坏死因子(TNF)、白细胞介素(IL)-6、IL-1β释放(P<0.05),显著降低神经小胶质细胞的数量(P<0.05),并显著改善了大脑海马体中细胞结构的紊乱，显著减少脑梗死面积，显著减轻脑水肿(P<0.05)。结论 Precedex能够通过降低TLR4/NF-κB炎症信号通路有效减轻脑缺血再灌注损伤。     

小胶质细胞焦亡与缺血性脑卒中的关系研究进展

<正>缺血性脑卒中是我国居民主要的死亡和致残原因,其中涉及到的病理生理过程复杂,主要包括氧化应激、兴奋性毒性、炎性反应等~([1-2])。近年来,越来越多的研究发现,由小胶质细胞焦亡介导的炎性反应可能是加剧脑缺血性损伤的重要因素。本研究对小胶质细胞焦亡与缺血性脑卒中的关系作一综述。1小胶质细胞功能与缺血性脑卒中小胶质细胞是中枢神经系统中负责免疫监视和吞噬功能的常驻免疫细胞,其介导的炎性反应是缺血性脑卒中重要的病理机制~([3-4])。在脑缺血性损伤早期,小胶质细胞迅速增殖活化,活化的小胶质细胞在形态和功能上与巨噬细胞相     

Toll-Like Receptors and Myocardial Ischemia/Reperfusion, Inflammation, and Injury

Cardiac ischemia/reperfusion (I/R) injury occurs in several important clinical contexts including percutaneous coronary interventions for acute myocardial ischemia, cardiac surgery in the setting of cardiopulmonary bypass, and cardiac transplantation. While the pathogenesis of I/R injury in these settings is multifactorial, it is clear that activation of the innate immune system and the resultant inflammatory response are important components of I/R injury. Toll-like receptor 4 (TLR4), originally identified as the sensor for bacterial lipopolysaccharide (LPS), has also been shown to serve as a sensor for endogenous molecules released from damaged or ischemic tissues. Accordingly, recent findings have demonstrated that TLR4 not only plays a central role as a mediator of cardiac dysfunction in sepsis, but also serves as a key mediator of myocardial injury and inflammation in the setting of I/R. Furthermore, TLR4 may play a role in the development of atherosclerotic lesions. Other studies have implicated TLR4 in the adverse remodeling that may occur after ischemic myocardial injury. This emerging body of literature, which is reviewed here, has provided new insight into the early molecular events that mediate myocardial injury and dysfunction in the setting of I/R injury.     

Matrix regulation of lung injury, inflammation, and repair: the role of innate immunity

Mechanisms that regulate host defense after noninfectious tissue injury are incompletely understood. Our laboratory is interested in the role of the extracellular matrix glycosaminoglycan hyaluronan in the regulation of lung inflammation and fibrosis. We have identified key roles for two cell surface receptor systems that interact with hyaluronan to control lung inflammation and tissue repair. Hematopoietic CD44 is necessary to clear hyaluronan fragments that are produced after lung injury. Failure to clear hyaluronan fragments leads to unremitting inflammation. However, in the absence of CD44, alveolar macrophages continue to produce chemokines in response to hyaluronan fragments, implicating another receptor system in controlling macrophage effector function. We found that Toll-like receptors 2 and 4 (TLR2 and TLR4) are responsible for macrophage inflammatory gene expression in response to hyaluronan fragments. Although TLR2 and TLR4 initiate the innate immune response in noninfectious inflammation, they have a protective role against lung injury on alveolar epithelial cells.     

Innate immunity to pneumococcal infection of the central nervous system depends on toll-like receptor (TLR) 2 and TLR4

Background. @nbsp; Recent studies have suggested that, in addition to Toll-like receptor (TLR) 2, other pattern recognition receptors mediate activation of the immune response after infection of the central nervous system (CNS) with Streptococcus pneumoniae (SP). Methods. @nbsp; Using a mouse meningitis model, we investigated the influence of TLR4 single deficiency (TLR4(-/-)), TLR2/TLR4 double deficiency (TLR2/4(-/-)), and TLR2/TLR4/TLR9 triple deficiency (TLR2/4/9(-/-)) on the immune response of the CNS to SP infection. To identify the cell populations that mediate the responses to SP, we generated TLR2/4(-/-)-wild-type (wt) bone marrow (BM) chimeras. Results. @nbsp; Compared with infected wt mice, infected TLR2/4(-/-) and TLR2/4/9(-/-) mice had similar reductions in brain cytokine levels, pleocytosis, and cerebral pathologic findings, whereas no such effect was noted in infected TLR4(-/-) mice. The attenuated immune response was paralleled by an impaired host defense that resulted in worsening of disease. Analysis of the chimeric mice after infection showed that mere TLR2/4 deficiency, either of radioresistant cells or of transplanted BM-derived cells, was sufficient to mount a substantial cerebral immune response, such as that noted in wt mice. Conclusion. @nbsp; In murine SP meningitis, TLR2 and TLR4 expressed on radioresistant and transplanted BM-derived cells were major cellular sensors of invading SP inducing inflammatory responses.     

Compartmentalized gene expression of toll‐like receptors 2, 4 and 9 in the brain and peripheral lymphoid organs during canine visceral leishmaniasis

Visceral leishmaniasis is an important parasitic disease that affects humans and animals. The response against the protozoan involves the interaction of both innate and adaptive branches of the immune system, and an important immune sensor is represented by the toll‐like receptor (TLR) family. Here, we investigated the pattern of TLR‐2, TLR‐4 and TLR‐9 gene expression in different compartments (brain, choroid plexus, spleen and lymph node) of dogs naturally infected with Leishmania infantum. Gene expression of the TLRs varied according to the compartment evaluated. In the brain, there was only an upregulation of TLR‐2, whereas in the choroid plexus, TLR‐2 and TLR‐9 were both upregulated. Further, the peripheral lymphoid organs (spleen and lymph nodes) showed increased TLR‐2 and TLR‐4 expression. This study provides the first insight about TLR expression in the central nervous system of infected dogs, and gives additional evidence of the compartmentalization of the immune response during visceral leishmaniasis.     

Toll样受体4与缺血性脑损伤

Toll样受体是天然免疫系统识别病原微生物的主要受体,在天然免疫反应中具有重要作用。Toll样受体4(TLR4)不仅是介导脂多糖信号跨膜转导的主要受体,而且也参与了缺血性损伤等非病原微生物性炎症反应。有关TLR4及其介导的信号转导在脑血管病中的作用日益引起人们的关注。深入研究TLR4在脑血管病中的作用,有可能为进一步揭示脑血管病的发病机制并为寻求有效的防治措施提供重要的理论基础。     

Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice

Background: Excessive alcohol intake causes an increase in intestinal permeability that induces translocation of gut‐derived lipopolysaccharide (LPS) to the portal vein. Increased LPS in the portal vein stimulates Kupffer cells through Toll‐like receptor (TLR) 4 in the liver. Activated TLR4 signaling in Kupffer cells induces various inflammatory mediators including TNF‐α, IL‐1β, and reactive oxygen species, resulting in liver injury. Hepatic stellate cells (HSCs) also express TLR4. This study investigates whether TLR4 on bone marrow (BM)‐derived cells, including Kupffer cells, or non–BM‐derived endogenous liver cells, including HSCs, contributes to the progression of alcohol‐induced steatohepatitis and fibrogenesis in mice. Methods: TLR4 BM chimera (wild‐type [WT] mice with TLR4^?/? BM or TLR4^?/? mice with WT BM) were generated by the combination of liposomal clodronate injection with whole body irradiation and BM transplantation, followed by treatment with intragastric alcohol feeding. Results: WT mice transplanted with WT BM exhibited liver injury, steatosis, inflammation, and a fibrogenic response. Conversely, TLR4^?/? mice with TLR4^?/? BM displayed less steatosis, liver injury, and inflammation. Notably, steatosis, macrophage infiltration, and alanine aminotransferase levels in both TLR4‐chimeric mice showed intermediate levels between WT mice transplanted with WT BM and TLR4^?/? mice transplanted with TLR4^?/? BM. Hepatic mRNA expression of fibrogenic markers (collagen α1(I), TIMP1, TGF‐β1) and inflammatory cytokines (IL‐1β, IL‐6) were markedly increased in WT mice with WT BM, but there was less of an increase in both TLR4‐chimeric mice and in TLR4^?/? mice transplanted with TLR4^?/? BM. Conclusions: TLR4 signaling in both BM‐derived and non–BM‐derived liver cells is required for liver steatosis, inflammation, and a fibrogenic response after chronic alcohol treatment.     

Toll样受体4在急性肺损伤炎症反应中的作用

Toll样受体4(TLR4)基因多态性与急性肺损伤原发病因免疫应答的启动及炎症反应程度有关,TLR4所介导生成的炎症介质是急性肺损伤炎症反应的分子基础.深入研究,ITLR4为代表的先天免疫与急性肺损伤炎症反应的关系将为揭示急性肺损伤的病理生理机制提供新的思路和手段.     

Does progesterone have neuroprotective properties?

In this article, we review published preclinical and epidemiologic studies that examine progesterone's role in the central nervous system. Its effects on the reproductive and endocrine systems are well known, but a large and growing body of evidence, including a recently published pilot clinical trial, indicates that the hormone also exerts neuroprotective effects on the central nervous system. We now know that it is produced in the brain, for the brain, by neurons and glial cells in the central and peripheral nervous system of both male and female individuals. Laboratories around the world have reported that administering relatively large doses of progesterone during the first few hours to days after injury significantly limits central nervous system damage, reduces loss of neural tissue, and improves functional recovery. Although the research published to date has focused primarily on progesterone's effects on blunt traumatic brain injury, there is evidence that the hormone affords protection from several forms of acute central nervous system injury, including penetrating brain trauma, stroke, anoxic brain injury, and spinal cord injury. Progesterone appears to exert its protective effects by protecting or rebuilding the blood-brain barrier, decreasing development of cerebral edema, down-regulating the inflammatory cascade, and limiting cellular necrosis and apoptosis. All are plausible mechanisms of neuroprotection.     

Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages

This study demonstrates that pretreatment with polyinosinic-polycytidylic acid (poly I:C) significantly decreased the mortality and liver injury caused by injection of lipopolysaccharide (LPS) in the presence of d-galactosamine (d-GalN) in C57BL/6 mice. Depletion of natural killer, natural killer T, and T cells did not change the protective effect of poly I:C on LPS/d-GalN-induced liver injury in vivo. However, depletion of macrophages abolished LPS/d-GalN-induced fulminant hepatitis, which could be restored by adoptive transfer of macrophages but not by transfer of poly I:C-treated macrophages. Treatment with poly I:C down-regulated the expression of the toll-like receptor 4 (TLR4) on macrophages and reduced the sensitivity of macrophages (Kupffer cells and peritoneal macrophages from C57BL/6 mice, or RAW264.7 cells) to LPS stimulation. Poly I:C pretreatment also impaired the signaling of mitogen-activated protein kinases and NF-kappaB induced by LPS in RAW264.7 cells. Blockade of TLR3 with a TLR3 antibody abolished poly I:C down-regulation of TLR4 expression and LPS stimulation of TNF-alpha production in RAW264.7 cells. Taken together, our findings suggest that activation of TLR3 by its ligand, poly I:C, induced LPS tolerance by down-regulation of TLR4 expression on macrophages.