Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis of TLR4 terminates the MyD88-dependent signaling, while the following endosome maturation and lysosomal degradation of TLR4 determine the duration and magnitude of the TRIF-dependent one. Alternatively, TLR4 may return to the plasma membrane, which process is still poorly understood. Therefore, the course of the LPS-induced pro-inflammatory responses depends strictly on the rates of TLR4 endocytosis and trafficking through the endo-lysosomal compartment. Notably, prolonged activation of TLR4 is linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer. Recent studies have provided ample data on the role of diverse proteins regulating the functions of early, late, and recycling endosomes in the TLR4-induced inflammation caused by LPS or phagocytosis of E. coli. In this review, we focus on the mechanisms of the internalization and intracellular trafficking of TLR4 and CD14, and also of LPS, in immune cells and discuss how dysregulation of the endo-lysosomal compartment contributes to the development of diverse human diseases.

Toll样受体（TLR）4属于TLR受体家族，可诱导对入侵病原体的促炎反应。TLR4被革兰氏阴性细菌的脂多糖（LPS，内毒素）激活并依次触发两个信号级联：第一个涉及TIRAP和MyD88衔接子蛋白的信号在质膜中被诱导，而第二个衔接衔接子蛋白TRAM和TRIF则在早期开始。内吞后受体内吞。LPS诱导的TLR4内在化，以及TRIF依赖性途径的激活也受GPI锚定的蛋白质CD14支配。TLR4的内吞作用终止了MyD88依赖的信号传导，而随后的内体成熟和TLR4的溶酶体降解决定了TRIF依赖的内在持续时间和强度。或者，TLR4可能返回质膜，这一过程仍知之甚少。因此，LPS诱导的促炎反应的过程严格取决于TLR4内吞和通过溶酶体区室运输的速率。值得注意的是，TLR4的长期激活与几种人类遗传疾病，神经退行性变以及自身免疫性疾病和癌症有关。最近的研究提供了充足的数据，说明各种蛋白质在调节早期，晚期和回收内体的功能在由LPS或吞噬作用引起的TLR4诱导的炎症中的作用。TLR4的长期激活与几种人类遗传疾病，神经退行性变以及自身免疫性疾病和癌症有关。最近的研究提供了充足的数据，说明各种蛋白质在调节早期，晚期和回收内体的功能在由LPS或吞噬作用引起的TLR4诱导的炎症中的作用。TLR4的长期激活与几种人类遗传疾病，神经退行性变以及自身免疫性疾病和癌症有关。最近的研究提供了充足的数据，说明各种蛋白质在调节早期，晚期和回收内体的功能在由LPS或吞噬作用引起的TLR4诱导的炎症中的作用。大肠杆菌。在这篇综述中，我们着眼于免疫细胞中TLR4和CD14以及LPS的内在化和细胞内运输的机制，并讨论了溶酶体区室的失调如何导致多种人类疾病的发展。