Cell Surface Expression of Endosomal Toll-Like Receptors—A Necessity or a Superfluous Duplication?

Abstract

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.

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“…For example, it has been reported that in cortical and hippocampal neurons where TLR7 is localised to the endosomes, stimulation with let‐7b, another TLR7 ligand, led to apoptosis (Lehmann et al., 2012), whereas in sensory neurons where TLR7 is localised to the plasma membrane, let‐7b binding led to stimulation of the cation channel transient receptor potential A1 (TRPA1) (Park et al., 2014). Similarly, TLR7 is expressed on both cell surface and endosomes in macrophages (Mielcarska et al., 2020), however it is exclusively present in endosomes in microglia (Kumar, 2019), therefore it is likely to see differences in ligand binding response between RAW 264.7 cells and WT‐MG.…”

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“…While it is well known that intracellular TLRs are physically separated from the cell surface to prevent autoimmune responses following receptor activation by host nucleic acids [74], interestingly, several studies have suggested the cell surface positioning of endosomal TLRs in certain cell types [75][76][77][78]. Cell surface expression of TLR3 was observed in human fibroblast cell lines [79], mouse splenic CD8 + dendritic cells, and marginal zone B cells [80].…”

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“…TLR2 and 4 recognize viruses at the cell surface, while TLR3 recognizes double-stranded (ds)RNA and TLR7 and 8 recognize single-stranded (ss)RNA, and TLR9 recognizes DNA with Unmethylated cytosine–guanine dinucleotide (CpG) motifs in the endosomes. Although it is not fully understood why, TLR3, TLR7, and TLR9 may occur both in the cell membrane and intracellularly [ 47 ]. TLRs may, in addition to apical and endosomal, include basolateral and basal cell membrane expression.…”