Division of Immunology, Institute of Veterinary Medicine, Department of Preclinical Sciences, Warsaw University of Life Sciences, Warsaw, Poland.
Center for Integrative Mammalian Research, Department of Biomedical Sciences, Ross University School of Veterinary Medicine, Basseterre, Saint Kitts and Nevis.
Front Immunol. 2021 Feb 1;11:620972. doi: 10.3389/fimmu.2020.620972. eCollection 2020.
Timely and precise delivery of the endosomal Toll-like receptors (TLRs) to the ligand recognition site is a critical event in mounting an effective antimicrobial immune response, however, the same TLRs should maintain the delicate balance of avoiding recognition of self-nucleic acids. Such sensing is widely known to start from endosomal compartments, but recently enough evidence has accumulated supporting the idea that TLR-mediated signaling pathways originating in the cell membrane may be engaged in various cells due to differential expression and distribution of the endosomal TLRs. Therefore, the presence of endosomal TLRs on the cell surface could benefit the host responses in certain cell types and/or organs. Although not fully understood why, TLR3, TLR7, and TLR9 may occur both in the cell membrane and intracellularly, and it seems that activation of the immune response can be initiated concurrently from these two sites in the cell. Furthermore, various forms of endosomal TLRs may be transported to the cell membrane, indicating that this may be a normal process orchestrated by cysteine proteases-cathepsins. Among the endosomal TLRs, TLR3 belongs to the evolutionary distinct group and engages a different protein adapter in the signaling cascade. The differently glycosylated forms of TLR3 are transported by UNC93B1 to the cell membrane, unlike TLR7, TLR8, and TLR9. The aim of this review is to reconcile various views on the cell surface positioning of endosomal TLRs and add perspective to the implication of such receptor localization on their function, with special attention to TLR3. Cell membrane-localized TLR3, TLR7, and TLR9 may contribute to endosomal TLR-mediated inflammatory signaling pathways. Dissecting this signaling axis may serve to better understand mechanisms influencing endosomal TLR-mediated inflammation, thus determine whether it is a necessity for immune response or simply a circumstantial superfluous duplication, with other consequences on immune response.
内体 Toll 样受体 (TLRs) 及时、精确地递送到配体识别位点是引发有效抗菌免疫反应的关键事件，然而，同一 TLRs 应保持避免识别自身核酸的微妙平衡。这种感应广泛认为始于内体隔室，但最近有足够的证据支持这样的观点，即起源于细胞膜的 TLR 介导的信号通路可能由于内体 TLRs 的差异表达和分布而参与各种细胞。因此，内体 TLRs 存在于细胞表面可能有益于某些细胞类型和/或器官中的宿主反应。尽管不完全清楚原因，但 TLR3、TLR7 和 TLR9 可能既存在于细胞膜上，也存在于细胞内，似乎可以从细胞的这两个部位同时启动免疫反应的激活。此外，各种形式的内体 TLRs 可能被转运到细胞膜，表明这可能是由半胱氨酸蛋白酶-组织蛋白酶协调的正常过程。在内体 TLRs 中，TLR3 属于进化上不同的组，并在信号级联中参与不同的蛋白质衔接器。TLR3 的不同糖基化形式通过 UNC93B1 转运到细胞膜，而 TLR7、TLR8 和 TLR9 则不同。本综述的目的是调和对内体 TLR 细胞表面定位的各种观点，并对内体 TLR 受体定位对其功能的影响增加视角，特别关注 TLR3。细胞膜定位的 TLR3、TLR7 和 TLR9 可能有助于内体 TLR 介导的炎症信号通路。剖析这一信号轴可能有助于更好地理解影响内体 TLR 介导的炎症的机制，从而确定它是否是免疫反应的必要条件，还是仅仅是偶然的多余复制，对免疫反应有其他影响。
