The Toll for Trafficking: Toll-Like Receptor 7 Delivery to the Endosome

Abstract

Toll-like receptor (TLR)-7 is an endosomal innate immune sensor capable of detecting single-stranded ribonucleic acid. TLR7-mediated induction of type I interferon and other inflammatory cytokine production is important in antiviral immune responses. Furthermore, altered TLR7 expression levels are implicated in various autoimmune disorders, indicating a key role for this receptor in modulating inflammation. This review is focused on the regulation of TLR7 expression and localization compared to that of the other endosomal TLRs: TLR3, 8, and 9. Endosomal TLR localization is a tightly controlled and intricate process with some shared components among various TLRs. However, TLR-specific mechanisms must also be in place in order to regulate the induction of pathogen- and cell-specific responses. It is known that TLR7 is shuttled from the endoplasmic reticulum to the endosome via vesicles from the Golgi. Several chaperone proteins are required for this process, most notably uncoordinated 93 homolog B1 (Caenorhabditis elegans), recently identified to also be involved in the localization of the other endosomal TLRs. Acidification of the endosome and proteolytic cleavage of TLR7 are essential for TLR7 signaling in response to ligand binding. Cleavage of TLR7 has been demonstrated to be accomplished by furin peptidases in addition to cathepsins and asparagine endopeptidases. Moreover, triggering receptor expressed on myeloid cells like 4, a protein associated with antigen presentation and apoptosis in immune cells, has been implicated in the amplification of TLR7 signaling. Understanding these and other molecular mechanisms controlling TLR7 expression and trafficking will give insight into the specific control of TLR7 activity compared to the other endosomal TLRs.

The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer

“…Following inflammatory stimuli, TLR7 is ubiquitinated and packaged into COPII-coated vesicles by the endoplasmic reticulum (ER)-resident chaperone UNC93B1 40,41 . Upon binding ssRNA, TLR7 signaling results in the production of proinflammatory cytokines and type I interferon, T-cell proliferation, and induction of T H 1 responses 42,43 . We observed many of these elements within PDAC tumors treated with R848, including CD8 + T-cell proliferation and effector function, and decreased T H 2 polarization among CD4 + T cells.…”

Modular bioinformatics analysis demonstrates that a Toll‑like receptor signaling pathway is involved in the regulation of macrophage polarization

“…The present results further suggested that TLR7 serves as a mediator of M2 macrophage polarization. In contrast to the well-known macrophage polarization-associated TLR transmembrane family members, including TLR4, TLR7 is localized in the endosomal compartment, along with TLR3/9, and is associated with the viral-induced immune response ( 46 ). A recent study demonstrated that Hepatitis C virus-induced TLR7 stimulation results in monocyte differentiation and M2 macrophage polarization ( 36 ), which is consistent with the present study and further suggests that TLR7 stimulated macrophage polarization associated with chronic liver disease pathogenesis.…”

Opposing roles of endosomal innate immunity proteins IFITM3 and TLR7 in human metapneumovirus infection

“…TLR7 is generally considered an antiviral molecule since it detects viral singlestranded RNA and signals for the production of type I IFNs [43]. TLR7 is expressed on macrophages, conventional dendritic cells, and plasmacytoid dendritic cells [43], and our work suggests that its presence makes these cell types more susceptible to infection with certain hMPV strains.…”

“…TLR7 is generally considered an antiviral molecule since it detects viral singlestranded RNA and signals for the production of type I IFNs [43]. TLR7 is expressed on macrophages, conventional dendritic cells, and plasmacytoid dendritic cells [43], and our work suggests that its presence makes these cell types more susceptible to infection with certain hMPV strains. Staining of primary human lung airway epithelial cells with anti-TLR7 antibodies also indicated that TLR7 is expressed on these cells [44], which are additional relevant targets of hMPV infection.…”