Treatment of endotoxin-induced tissue damages by the negative regulation of TLR-mediated signal pathways

免疫主要分为两种类型，过继免疫和先天免疫。与天然免疫相比，获得性免疫具有识别相应抗原的多样性和准确性，这是基于T细胞和B细胞选择性地具有的DNA重排机制和超突变特性。因此，获得性免疫被认为是一种非常复杂和理想的宿主防御系统。先天性免疫一直被认为只是作为前线发挥作用，在相应的获得性免疫激活后就会退出。事实上，先天性免疫成分，如树突状细胞（DC）和巨噬细胞，可以迅速响应微生物及其产物，而无需额外的获得性免疫应答的帮助，而获得性免疫需要很长时间才能发挥其全部免疫作用。然而，最近对先天免疫系统中信号受体的深入研究，特别是对Toll样受体的研究， ...更多信息 ptors（TLR）的研究，使我们注意到其重要性与适应性免疫相当。微生物感染后，抗原呈递细胞（APC）组成先天免疫捕获微生物抗原。同时，微生物产物通过它们的TLR刺激APC经历适当的成熟，这由对于易位到局部淋巴结中至关重要的趋化因子受体和对于T辅助细胞的适当活化所必需的各种共刺激分子的表达表示。这些APC也响应微生物的TLR配体产生多种细胞因子。除非它们通过TLR经历这些生物学事件，否则这些APC不能驱动抗原特异性T细胞的活化或分化。特别地，由APC产生的某些细胞因子，如IL-12和IL-18，是幼稚辅助T细胞向效应细胞分化以根除微生物所需的。因此，先天免疫应答的缺乏使得哺乳动物宿主对病理生物体高度易感。先天免疫配备有各种信号受体，包括TLR家族（Janeway和Medzhitov，2002）。TLR家族由10多个成员组成。每个成员精确地识别与病原体相关的相应分子模式，并基于它们对宿主来源的完整组分的无知而发挥其宿主防御作用。事实上，TLR介导的信号通路对于感染早期的微生物驱逐是必不可少的。出乎意料的是，重要的是，通过TLR的信号传导对于随后的获得性免疫的激活是绝对需要的。缺乏TLR介导的途径有时会导致不成熟的T细胞应答和记忆T细胞发育失败，这可能是由于缺乏细胞因子产生和DC成熟和活化，这通常是由TLR途径的活化诱导的，并且是那些免疫事件所需的。先天免疫的过度激活会导致疾病。有充分的证据表明，病原体激活先天免疫偶尔会通过细胞因子的异常诱导引起致命的病理改变。先天性和获得性免疫系统都通过同源细胞相互作用和细胞因子捕获碗完成其适当的行动。因此，通过调节TLR和细胞因子信号通路来调节先天免疫和获得性免疫，对于机体的稳态免疫应答具有重要意义。在部分肝切除术后，野生型小鼠显示出迅速的肝再生。然而，缺乏TLR介导通路激活所必需的细胞内衔接分子的突变小鼠在部分肝切除后的肝再生中存在缺陷。这清楚地表明TLR介导的先天免疫不仅对宿主防御而且对组织稳态都是必不可少的。此外，我们观察到，IL-6，而不是TNF，这两者都是由TLR介导的信号激活诱导的，有助于小鼠急性反应性关节炎的发展。因此，这些结果表明TLR介导的途径在各种生物学情况下发挥重要作用，如宿主防御，组织稳态和偶然的组织损伤。少

Immunity is largely categorized into two types, adoptive immunity and innate immunity. As compared with innate immunity, acquired immunity has the diversity and the accuracy in its recognition of corresponding antigens based on the DNA rearrangement machineries and hypermutation properties that T cells and B cells selectively possess. Therefore, acquired immunity had been believed to he extremely sophisticated and ideal system for host defense. Innate immunity had been regarded to play a role only as the front line that would drop out after activation of the corresponding acquired immunity. In fact, innate immune constituents, such as dendritic cells(DCs) and macrophages, can promptly respond to microbes and their products without help from additional acquired immune responses, whereas acquired immunity takes long time to be able to exert its full immunological actions. However, recent intensive studies on signaling receptors in the innate immune system, in particular on toll-like rece … More ptors(TLRs), led us to notify its importance comparable to adaptive immunity. After microbial infection, antigen-presenting cells(APCs) composing innate immunity capture the microbial antigens. Simultaneously, the microbial products stimulate the APCs through their TLRs to undergo the appropriate maturation, which is represented by expression of chemokine receptors critical for translocation into the regional lymph nodes and of various co-stimulatory molecules essential for the appropriate activation of T helper cells. These APCs produce a variety of cytokines in response to the TLR ligands of the microbes as well. Unless they experience these biological events through their TLRs, these APCs cannot drive the activation or differentiation of antigen-specific T cells. In particular, certain cytokines, such as IL-12 and IL-18, produced by the APCs are required for the differentiation of naive helper T cells toward the effector cells to eradicate the microbes. Thus, the absence of innate immune responses render mammalian host highly susceptible to pathological organisms.Innate immunity is equipped with various signaling receptors including a TLR family (Janeway and Medzhitov,2002). TLR family consists of more than 10 members. Each member precisely recognizes corresponding molecular patterns associated with pathogens, and exerts its host defensive actions based on their ignorance of host-derived intact components. Indeed, the TLR-mediated signal pathways are essential for microbe expulsion at the early infectious phase. Unexpectedly and importantly, the signalings through TLRs are definitely required for the following activation of the acquired immunity. Lack of the TLR-mediated pathway sometimes causes immature T cell responses and failure in the development of memory T cells, presumably due to the absence of cytokine production and DC maturation and activation, which is normally induced by the activation of the TLR pathway and is required for those immunological events.Like in the case of autoimmunity associated with the dysregulated adaptive immunity, excessive activation of innate immunity causes diseases. It is well documented that the activation of innate immunity by pathogens occasionally causes fatal pathological alterations via aberrant induction of cytokines. Both innate and acquired immune systems complete their proper actions via cognate cellular interactions and cytokine catch bowl. Therefore, it is quite important for homeostatic immune responses to regulate the innate immune responses and adaptive immunity by controlling TLR and cytokine signalings.In this study, we demonstrated that TLR-mediated signaling are essential for the tissue homeostasis in mice. Upon partial hepatectomy, wild-type mice show prompt liver regeneration. However, mutant mice that lack intracellular adaptor molecule essential for the activation of TLR-mediated pathways are defect in the liver regeneration after partial hepatectomy. This clearly indicates that TLR-mediated innate immunity is essential for not only host defense but also tissue homeostasis. Furthermore, we observed that IL-6 but not TNF, both of which are induced by the activation of TLR-mediated signalings, contributes to the development of acute reactive arthritis in mice. Thus, these results indicate that the TLR-mediated pathways play an important role in various biological situations, such as host defense, tissue homeostasis and incidental tissue injuries. Less