Department of Cardiovascular Sciences, Glenfield General Hospital, University of Leicester, Leicester, UK, LE3 9QP.
J Leukoc Biol. 2010 Jun;87(6):989-99. doi: 10.1189/jlb.1209775. Epub 2010 Feb 23.
The mammalian TLRs serve as key sensors of PAMPs, such as bacterial LPS, lipopeptides, and flagellins, which are present in microbial cells but not host cells. TLRs have therefore been considered to play a central role in the discrimination between "self" and "non-self". However, since the discovery of their microbial ligands, many studies have provided evidence that host-derived molecules may also stimulate TLR2- or TLR4-dependent signaling. To date, more than 20 of these endogenous TLR ligands have been proposed, which have tended to fall into the categories of released intracellular proteins, ECM components, oxidatively modified lipids, and other soluble mediators. This review aims to summarize the evidence supporting the intrinsic TLR-stimulating capacity of each of these proposed endogenous ligands with a particular emphasis on the measures taken to exclude contaminating LPS and lipopeptides from experimental systems. The emerging evidence that many of these molecules may be more accurately described as PAMP-binding molecules (PBMs) or PAMP-sensitizing molecules (PSMs), rather than genuine ligands of TLR2 or TLR4, is also summarized. The relevance of this possibility to the pathogenesis of chronic inflammatory diseases, tumor surveillance, and autoimmunity is discussed.
哺乳动物的 TLR 作为 PAMP 的关键传感器，如细菌 LPS、脂肽和鞭毛蛋白，这些物质存在于微生物细胞中而不存在于宿主细胞中。因此，TLR 被认为在区分“自我”和“非自我”方面发挥着核心作用。然而，自从发现它们的微生物配体以来，许多研究已经提供了证据表明，宿主来源的分子也可能刺激 TLR2 或 TLR4 依赖性信号转导。迄今为止，已经提出了超过 20 种这些内源性 TLR 配体，这些配体往往属于释放的细胞内蛋白、ECM 成分、氧化修饰的脂质和其他可溶性介质。本综述旨在总结支持这些内源性配体固有 TLR 刺激能力的证据，特别强调排除实验系统中污染 LPS 和脂肽的措施。还总结了许多这些分子可能更准确地描述为 TLR2 或 TLR4 的 PAMP 结合分子 (PBM) 或 PAMP 敏化分子 (PSM)，而不是真正的配体的这一新兴证据。还讨论了这种可能性与慢性炎症性疾病、肿瘤监测和自身免疫的发病机制的相关性。
