Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
Exp Mol Med. 2013 Feb 22;45(2):e11. doi: 10.1038/emm.2013.28.
Toll-like receptors (TLRs) are pivotal components of the innate immune response, which is responsible for eradicating invading microorganisms through the induction of inflammatory molecules. These receptors are also involved in responding to harmful endogenous molecules and have crucial roles in the activation of the innate immune system and shaping the adaptive immune response. However, TLR signaling pathways must be tightly regulated because undue TLR stimulation may disrupt the fine balance between pro- and anti-inflammatory responses. Such disruptions may harm the host through the development of autoimmune and inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Several studies have investigated the regulatory pathways of TLRs that are essential for modulating proinflammatory responses. These studies reported several pathways and molecules that act individually or in combination to regulate immune responses. In this review, we have summarized recent advancements in the elucidation of the negative regulation of TLR signaling. Moreover, this review covers the modulation of TLR signaling at multiple levels, including adaptor complex destabilization, phosphorylation and ubiquitin-mediated degradation of signal proteins, manipulation of other receptors, and transcriptional regulation. Lastly, synthetic inhibitors have also been briefly discussed to highlight negative regulatory approaches in the treatment of inflammatory diseases.
Toll 样受体 (TLRs) 是先天免疫反应的关键组成部分，通过诱导炎症分子来消除入侵的微生物。这些受体还参与对有害内源性分子的反应，并在先天免疫系统的激活和适应性免疫反应的形成中发挥关键作用。然而，TLR 信号通路必须受到严格调控，因为过度的 TLR 刺激可能会破坏促炎和抗炎反应之间的微妙平衡。这种破坏可能会通过自身免疫和炎症性疾病（如类风湿关节炎和系统性红斑狼疮）的发展而伤害宿主。多项研究已经研究了调节 TLR 的调控途径，这些途径对于调节促炎反应至关重要。这些研究报告了几个单独或联合作用以调节免疫反应的途径和分子。在这篇综述中，我们总结了阐明 TLR 信号负调控的最新进展。此外，这篇综述涵盖了 TLR 信号在多个水平上的调节，包括衔接复合物的不稳定、信号蛋白的磷酸化和泛素介导的降解、其他受体的操纵以及转录调节。最后，还简要讨论了合成抑制剂，以突出在炎症性疾病治疗中采用的负调控方法。
