TLR7- cluster of differentiation 287

Toll-like receptor 7 (TLR7), is an immune gene possessed by humans, other mammals and additionally in avian species playing a significant role in initiating antiviral immune responses. It belongs to the evolutionarily conserved Toll-like receptor family. The TLR7 sequence encodes a 1049 amino acid protein with a calculated molecular weight of 121 kDa. Like all other members of the TLR family, TLR7 contain an ectodomain with multiple leucine-rich repeats (LRRs) and a cytoplasmic domain homologous to that of the human interleukin-1 (IL-1) receptor. TLR7 is most closely related to TLR8 and TLR9 with 43% and 36% overall amino acid sequence identity, respectively and thus along with TLR8 and TLR9 constitutes a new sub-family of the TLRs.

In vivo, TLR7 mRNA is expressed in lung, placenta, spleen, lymph node, and tonsil. TLR7 mRNA expression is highest in monocytes, B cells, and DC. In vitro, TLR7 mRNA expression is upregulated in THP-1 cells upon PMA-induced differentiation. TLR7 is highly upregulated by exposure to IL-6 and to a slightly lesser extent by autocrine IFN-γ, IL-1β. TLR7 mRNA expression in THP-1 cells is elevated after exposure to both Gram-positive and Gram-negative bacteria. Ex vivo, expression of TLR7 is elevated after exposure to both Gram-positive and Gram-negative bacteria in monocytes and to a greater degree in granulocytes. Like TLR3, it appears that TLR7 may be localized intracellularly (1, 2). In humans, TLR7 is expressed on a restricted range of cell types with the highest abundance found on plasmacytoid dendritic cells and B cells.

TLR7 is activated by infections with single-stranded RNA viruses, including influenza virus and vesicular stomatitis virus (VSV). Stimulation of TLR7 with the viral nucleic acids, causes a type I IFN response and secretion of a large quantity of IFNα and the production of inflammatory cytokines [including IFN-alpha, IFN-beta, interleukin-6 (IL-6), IL-12, tumour necrosis factor-alpha (TNF-alpha)]. TLR7 activation also mediates up-regulation of costimulatory molecules (CD40, CD80, CD86), major histocompatibilty complex molecules and chemokine receptors (CCR7) (3). Two signaling pathways of TLR7 are thought to induce inflammatory cytokine expression: the MyD88- IRAK1-TRAF6-IRF5 pathway and the MyD88-TRAF6-TAK1-MAPK/IKK-AP-1/NF-κB pathway.(4) Following nucleic acid recognition, TLR7 recruit the TIR-domain

containing adapter called MyD88. MyD88 forms a complex with members of IRAK family

(IRAK1 and IRAK4) and TRAF6, which in turn activates TAK1 and results in the activation of NF-κB. In addition to single-stranded RNA, the synthetic imidazoquinoline, imiquimod, a low molecular weight immune response modifier, activates TLR7 in both humans and mice, whereas its derivative resiquimod (R-848) activates TLR7 in humans. Both imiquimod and R-848 elicit robust anti-viral and anti-tumor immune responses in vivo, which correlate with a strong induction of type I IFNs. As a consequence of this activity, imiquimod is used for the treatment of external genital warts caused by human Papillomavirus. (5)  TLR7 has been implicated in recognizing guanosine and uracil-rich single-stranded(ss) RNA such as the U5 region of human immunodeficiency virus type 1 RNA and influenza U-rich ssRNA, leading to up-regulation of IFN-alpha

Reference:

1. Heine, H. & E. Lein (2003) Int. Arch. Allergy Immunol. 130:180.

2. Dunne, A. & L.A.J. O'Neill (2003) Sci. STKE 2003:re3.

3. Victoria J Volume 114 Issue 4 Page 507-521, April 2005

4. Myeong Sup Lee Annual Review of BiochemistryVol. 76: 447-480, 2007.

5. Annett Schoenemeyer J. Biol. Chem., Vol. 280, Issue 17, 17005-17012, April 29, 2005.