Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Avda, Atenas S/n, 28922, Alcorcón, Spain.
Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Universidad Rey Juan Carlos, Avda, Atenas S/n, 28922, Alcorcón, Spain.
Eur J Pharmacol. 2020 May 5;874:172975. doi: 10.1016/j.ejphar.2020.172975. Epub 2020 Feb 1.
Toll-like receptor 4 (TLR4) is expressed in a wide variety of cells and is the central component of the mammalian innate immune system. Since its discovery in 1997, TLR4 has been assigned an ever-increasing number of functions that extend from pathogen recognition to tissue damage identification and promotion of the intrinsic "damage repair response" in pain, intestinal, respiratory and vascular disorders. Precisely, the finding of conserved sequence homology among species along with the molecular and functional characterisation of the TLR4 gene enabled researchers to envisage a common operating system in the activation of innate immunity and the initiation of plastic changes at the onset of chronic pain. Malfunctioning in other conditions was conceived in parallel. In this respect, "pivot" proteins and pathway redundancy are not just evolutionary leftovers but essential for normal functioning or cell survival. Indeed, at present, TLR4 single nucleotide polymorphisms (SNP) and their association with certain dysfunctions and diseases are being confirmed in different pools of patients. However, despite its ability to trigger pathogen infection or alternatively tissue injury communications to immune system, TLR4 targeting might not be considered a panacea. This review article represents a compilation of what we know about TLR4 from clinics and basic research on the 20th anniversary of its discovery. Understanding how to fine-tune the interaction between TLR4 and its specific ligands may lead in the next decades to the development of promising new treatments, reducing polypharmacy and probably having an impact on drug use in numerous pathologies.
Toll 样受体 4（TLR4）在多种细胞中表达，是哺乳动物固有免疫系统的核心组成部分。自 1997 年发现以来，TLR4 的功能不断增加，从病原体识别延伸到组织损伤识别，并促进疼痛、肠道、呼吸和血管疾病中的固有“损伤修复反应”。确切地说，物种之间保守序列同源性的发现，以及 TLR4 基因的分子和功能特征，使研究人员能够设想固有免疫的激活和慢性疼痛开始时的可塑性变化具有共同的操作系统。在其他情况下的功能障碍也是如此。在这方面，“枢轴”蛋白和途径冗余不仅是进化的遗留物，而且对于正常功能或细胞存活是必不可少的。事实上，目前，TLR4 单核苷酸多态性（SNP）及其与某些功能障碍和疾病的关联正在不同患者群体中得到证实。然而，尽管 TLR4 能够引发病原体感染或组织损伤通讯以激活免疫系统，但 TLR4 靶向治疗可能不会被视为万能药。本文是在 TLR4 发现 20 周年之际，对其从临床和基础研究方面的了解进行的综述。了解如何微调 TLR4 与其特定配体之间的相互作用，可能会在未来几十年内开发出有前途的新治疗方法，减少多药治疗，并可能对众多疾病的药物使用产生影响。
