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Toll-like Receptors in Innate Immunity 先天免疫中的toll样受体
Pub Date : 2021-08-23 DOI: 10.9734/bpi/mono/978-93-91882-59-4/ch1
N. Hadi, S. Shaker, Nada R. Alharis
Innate immunity is present in both vertebrates and invertebrates, raising the possibility that investigation of host defense mechanisms in model organisms prone to genetic analysis, such as the fruit fly Drosophila, may shed light on the nature of the elusive Pattern Recognition Receptors. The family of Toll-like receptors plays an essential role in the induction of the immune response. These receptors sense the presence of microbial ligands and activate the nuclear factor-_B transcription factor. The name of Toll-like receptors comes from the vernacular German Toll, meaning super or fantastic. Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity.
先天免疫存在于脊椎动物和无脊椎动物中,这提高了对易于进行遗传分析的模式生物(如果蝇)中宿主防御机制的研究的可能性,可能会揭示难以捉摸的模式识别受体的本质。toll样受体家族在诱导免疫应答中起着重要作用。这些受体感知微生物配体的存在并激活核因子-_B转录因子。Toll样受体的名字来自德语方言Toll,意思是超级的或奇妙的。toll样受体(TLRs)的功能表征表明,先天免疫是一种检测微生物病原体入侵的熟练系统。TLRs对微生物成分的识别启动信号转导通路,从而触发基因的表达。这些基因产物控制先天免疫反应,并进一步指导抗原特异性获得性免疫的发展。
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引用次数: 4
Signaling Danger: Toll-Like Receptors and Their Potential Roles in Diseases 信号危险:toll样受体及其在疾病中的潜在作用
Pub Date : 2021-08-23 DOI: 10.9734/bpi/mono/978-93-91882-59-4/ch5
N. Hadi, S. Shaker, Nada R. Alharis
Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy).  The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established.  An important contributor to microglial activation is toll-like receptor 4, a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli.
toll样受体(TLR)是一个新兴的受体家族,可识别病原体相关的分子模式并促进白细胞和内在肾细胞的激活。TLR的配体包括外源性微生物成分,如LPS (TLR4)、脂蛋白和肽聚糖(TLR1, -2, -6)、病毒RNA (TLR3)、细菌和病毒未甲基化的胞嘧啶-鸟苷二核苷酸(CpG)-DNA (TLR9),以及内源性分子,包括热休克蛋白和细胞外基质分子。受到刺激后,TLR通过与白细胞介素-1受体共享的myd88依赖性和myd88非依赖性信号通路诱导炎症细胞因子或共刺激分子的表达。TLR在白细胞亚群和非免疫细胞上有差异表达,似乎调节先天和适应性免疫反应的重要方面。小管上皮细胞是表达TLR1、-2、-3、-4和-6的非免疫细胞之一,这表明这些TLR可能在小管间质损伤(如细菌性肾盂肾炎、败血症和移植肾病)中促进免疫反应的激活。toll样受体作为我们微生物防御系统的主要部分的作用已经在几项研究中得到证实,但它们作为过敏和哮喘介质的可能功能仍有待确定。小胶质细胞激活的一个重要因素是toll样受体4,这是一种病原体相关的分子模式受体,已知在响应各种中枢神经系统刺激时启动炎症级联反应。
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引用次数: 0
Emerging Role of Toll-like Receptors in Atherosclerosis toll样受体在动脉粥样硬化中的新作用
Pub Date : 2021-08-23 DOI: 10.9734/bpi/mono/978-93-91882-59-4/ch4
N. Hadi, S. Shaker, Nada R. Alharis
Atherosclerosis, the leading cause of cardiovascular disease (CVD), is driven by inflammation. Increasing evidence suggests that toll-like receptors (TLRs) are key orchestrators of the atherosclerotic disease process. Interestingly, a distinct picture is being revealed for individual receptors in atherosclerosis. TLRs exhibit a complex nature enabling the detection of multiple motifs named danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Activation of these receptors triggers an intracellular signalling cascade mediated through MyD88 or TRIF, leading to the production of pro- and anti-inflammatory cytokines. Inflammation drives atherosclerosis. Both immune and resident vascular cell types are involved in the development of atherosclerotic lesions. The phenotype and function of these cells are key in determining the development of lesions. Toll-like receptors are the most characterised innate immune receptors and are responsible for the recognition of exogenous conserved motifs on pathogens, and, potentially, some endogenous molecules. Both endogenous and exogenous TLR agonists may be present in atherosclerotic plaques. Engagement of toll-like receptors on immune and resident vascular cells can affect atherogenesis as signalling downstream of these receptors can elicit proinflammatory cytokine release, lipid uptake, and foam cell formation and activate cells of the adaptive immune system.
动脉粥样硬化是心血管疾病(CVD)的主要原因,是由炎症驱动的。越来越多的证据表明toll样受体(TLRs)是动脉粥样硬化疾病过程的关键协调者。有趣的是,动脉粥样硬化中个体受体的不同情况正在显现。tlr表现出复杂的性质,能够检测称为危险相关分子模式(DAMPs)和病原体相关分子模式(PAMPs)的多个基元。这些受体的激活触发通过MyD88或TRIF介导的细胞内信号级联,导致促炎和抗炎细胞因子的产生。炎症导致动脉粥样硬化。免疫和常驻血管细胞类型都参与了动脉粥样硬化病变的发展。这些细胞的表型和功能是决定病变发展的关键。toll样受体是最具特征的先天免疫受体,负责识别病原体上的外源性保守基元,并可能识别一些内源性分子。内源性和外源性TLR激动剂可能存在于动脉粥样硬化斑块中。toll样受体与免疫和常驻血管细胞的接触可以影响动脉粥样硬化,因为这些受体的下游信号可以引发促炎细胞因子释放、脂质摄取和泡沫细胞形成,并激活适应性免疫系统的细胞。
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引用次数: 15
Role of Toll-like Receptors in Health and Diseases of Gastrointestinal Tract toll样受体在胃肠道健康和疾病中的作用
Pub Date : 2021-08-23 DOI: 10.9734/bpi/mono/978-93-91882-59-4/ch3
N. Hadi, S. Shaker, Nada R. Alharis
The human gastrointestinal (GI) tract is colonized by non-pathogenic commensal microflora and frequently exposed to many pathogenic organisms. For the maintenance of GI homeostasis, the host must discriminate between pathogenic and non-pathogenic organisms and initiate effective and appropriate immune and inflammatory responses. Mammalian toll-like receptors (TLRs) are members of the pattern recognition receptor (PRR) family that plays a central role in the initiation of innate cellular immune responses and the subsequent adaptive immune responses to microbial pathogens. Recent studies have shown that gastrointestinal epithelial cells express almost all TLR subtypes characterized to date and that the expression and activation of TLRs in the GI tract are tightly and coordinately regulated. Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous luminal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system.  Gastric epithelial cells represent the first line of innate immune defence against H. pylori, and respond to infection by initiating numerous cell signalling cascades, resulting in cytokine induction and the subsequent recruitment of inflammatory cells to the gastric mucosa. Pathogen recognition receptors of the Toll-like receptor (TLR) family mediate many of these cell signalling events.
人类胃肠道(GI)是由非致病性共生菌群定植的,经常暴露于许多致病性微生物。为了维持胃肠道稳态,宿主必须区分致病和非致病生物,并启动有效和适当的免疫和炎症反应。哺乳动物toll样受体(TLRs)是模式识别受体(PRR)家族的成员,在先天细胞免疫反应的启动和随后对微生物病原体的适应性免疫反应中起着核心作用。最近的研究表明,胃肠道上皮细胞表达迄今为止所表征的几乎所有TLR亚型,并且TLR在胃肠道中的表达和激活受到紧密和协调的调节。炎症性肠病(IBD)中肠道炎症反应的启动和持续可能是由于肠道上皮对内源性肠道细菌菌群的过度防御反应。肠上皮细胞系组成性地表达几种功能性toll样受体(TLRs),这些受体似乎是先天反应系统的关键调节因子。胃上皮细胞是抵御幽门螺杆菌的第一道天然免疫防线,并通过启动大量细胞信号级联反应来应对感染,导致细胞因子诱导和随后的炎症细胞募集到胃粘膜。toll样受体(TLR)家族的病原体识别受体介导了许多这些细胞信号传导事件。
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引用次数: 0
Toll-like Receptor Signaling Pathways toll样受体信号通路
Pub Date : 2021-08-23 DOI: 10.9734/bpi/mono/978-93-91882-59-4/ch2
N. Hadi, S. Shaker, Nada R. Alharis
Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-kB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. The main players in innate immunity are phagocytes such as neutrophils, macrophages, and dendritic cells. These cells can discriminate between pathogens and self by utilizing signals from the Toll-like receptors (TLRs)1. TLRs recognize conserved motifs predominantly found in microorganisms but not in vertebrates. Stimulation of TLRs causes an immediate defensive response, including the production of an array of antimicrobial peptides and cytokines. Accumulating evidence has shown that individual TLRs can activate overlapping as well as distinct signaling pathways, ultimately giving rise to distinct biological effects.
toll样受体(TLRs)通过识别来自各种微生物的病原体相关分子模式在先天免疫系统中起着至关重要的作用。TLRs通过募集特异性接头分子发出信号,导致转录因子NF-kB和irf的激活,这决定了先天免疫应答的结果。在过去的十年中,TLR信号传导的确切机制已经通过各种方法被阐明,包括遗传、生化、结构、细胞生物学和生物信息学研究。TLR信号似乎是发散的,并且在针对特定病原体的先天免疫反应的许多方面发挥重要作用。先天免疫的主要参与者是吞噬细胞,如中性粒细胞、巨噬细胞和树突状细胞。这些细胞可以利用toll样受体(TLRs)的信号来区分病原体和自身。tlr识别的保守基序主要存在于微生物中,而不存在于脊椎动物中。刺激tlr会引起立即的防御反应,包括一系列抗菌肽和细胞因子的产生。越来越多的证据表明,单个tlr可以激活重叠的和不同的信号通路,最终产生不同的生物学效应。
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引用次数: 0
Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases toll样受体的重要方面:疾病中的信号通路
Pub Date : 2021-08-23 DOI: 10.9734/bpi/mono/978-93-91882-59-4
N. Hadi, S. Shaker, Nada R. Alharis
Toll-like receptors (TLRs) are an important family of receptors that constitute the first line of defense system against microbes. They can recognize both invading pathogens and endogenous danger molecules released from dying cells and damaged tissues and play a key role in linking innate and adaptive immunity. TLRs are widely distributed in both immune and other body cells. The expressions and locations of TLRs are regulated in response to specific molecules derived from pathogens or damaged host cells. The binding of ligands to TLR activates specific intracellular signaling cascades that initiate host defense reactions. Recent studies have shown that gastrointestinal epithelial cells express almost all TLR subtypes characterized to date and that the expression and activation of TLRs in the GI tract are tightly and coordinately regulated. Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous luminal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system.  Gastric epithelial cells represent the first line of innate immune defence against H. pylori, and respond to infection by initiating numerous cell signalling cascades, resulting in cytokine induction and the subsequent recruitment of inflammatory cells to the gastric mucosa. Pathogen recognition receptors of the Toll-like receptor (TLR) family mediate many of these cell signalling events. Engagement of toll-like receptors on immune and resident vascular cells can affect atherogenesis as signalling downstream of these receptors can elicit proinflammatory cytokine release, lipid uptake, and foam cell formation and activate cells of the adaptive immune system. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy).  The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. An important contributor to microglial activation is toll-like receptor 4, a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli.
toll样受体(TLRs)是一类重要的受体,是机体抵御微生物的第一道防线。它们既可以识别入侵的病原体,也可以识别从死亡细胞和受损组织释放的内源性危险分子,在连接先天免疫和适应性免疫中发挥关键作用。tlr广泛分布于免疫细胞和其他身体细胞中。tlr的表达和位置受到来自病原体或受损宿主细胞的特定分子的调节。配体与TLR的结合激活了特异性的细胞内信号级联反应,从而启动宿主防御反应。最近的研究表明,胃肠道上皮细胞表达迄今为止所表征的几乎所有TLR亚型,并且TLR在胃肠道中的表达和激活受到紧密和协调的调节。炎症性肠病(IBD)中肠道炎症反应的启动和持续可能是由于肠道上皮对内源性肠道细菌菌群的过度防御反应。肠上皮细胞系组成性地表达几种功能性toll样受体(TLRs),这些受体似乎是先天反应系统的关键调节因子。胃上皮细胞是抵御幽门螺杆菌的第一道天然免疫防线,并通过启动大量细胞信号级联反应来应对感染,导致细胞因子诱导和随后的炎症细胞募集到胃粘膜。toll样受体(TLR)家族的病原体识别受体介导了许多这些细胞信号传导事件。toll样受体与免疫和常驻血管细胞的接触可以影响动脉粥样硬化,因为这些受体的下游信号可以引发促炎细胞因子释放、脂质摄取和泡沫细胞形成,并激活适应性免疫系统的细胞。小管上皮细胞是表达TLR1、-2、-3、-4和-6的非免疫细胞之一,这表明这些TLR可能在小管间质损伤(如细菌性肾盂肾炎、败血症和移植肾病)中促进免疫反应的激活。toll样受体作为我们微生物防御系统的主要部分的作用已经在几项研究中得到证实,但它们作为过敏和哮喘介质的可能功能仍有待确定。小胶质细胞激活的一个重要因素是toll样受体4,这是一种病原体相关的分子模式受体,已知在响应各种中枢神经系统刺激时启动炎症级联反应。
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Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases
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