Disease relevance of Tlr3

• Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells [1].
• A role for Toll-like receptor 3 (TLR3) was hypothesized in this context as viral double-stranded RNA (dsRNA) activates dendritic cells to secrete type I interferons and cytokines that are known to be associated with the disease activity in systemic lupus erythematosus (SLE) [1].
• Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis [2].
• Splenomegaly developing between 8 and 10 weeks of age was observed in tlr3(/) and tlr3(/)pkr(/) mice but not in wild-type or pkr(/) mice [3].
• After stimulation of mast cells with poly(I:C) and Newcastle disease virus (NDV), TLR3 is phosphorylated and the expression of key antiviral response cytokines (interferon beta, ISG15) and chemokines (IP10, RANTES) is upregulated [4].

High impact information on Tlr3

• Tumor necrosis factor-alpha receptor 1 signaling is vital for blood-brain barrier compromise upon Tlr3 stimulation by dsRNA or WNV [2].
• In unstimulated cells, neither CD14 nor TLR3 was detected in the lysosomes [5].
• The Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid, was used to activate innate immunity cells and mediators, including natural killer cells and interferon gamma [6].
• Murine cytomegalovirus (MCMV) infection and the TLR3 ligand polyinosinic-polycytidylic acid [poly(I:C)] were used to activate innate immunity [7].
• This report analyzes the effects of activation of innate immunity by viral infection or the toll-like receptor 3 (TLR3) ligand on liver regeneration [7].

Chemical compound and disease context of Tlr3

• Potential role of toll-like receptor 3 in a murine model of polyinosinic-polycytidylic acid-induced embryo resorption [8].

Biological context of Tlr3

• An anti-IFN-beta neutralizing antibody partially inhibited poly(I):poly(C)-induced CXCL10 mRNA, TLR3 mRNA and STAT1 phosphorylation [9].
• It is likely this phenotype is a result of TLR3 deficiency in combination with an additional, uncharacter-ized genetic defect or the presence of an infectious agent [3].
• Palpably enlarged cervical, axillary, and inguinal lymph nodes accompanied by enlarged spleens were observed in 12-18-week-old tlr3(/) mice at a higher frequency compared with other genotypes [3].
• Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages [10].
• Toll-like receptor 3 promotes cross-priming to virus-infected cells [11].

Anatomical context of Tlr3

• Peripheral WNV infection led to a breakdown of the blood-brain barrier and enhanced brain infection in wild-type but not in Tlr3(-/-) mice, although both groups were equally susceptible upon intracerebroventricular administration of the virus [2].
• Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to initiate antiviral signaling [12].
• The enlarged spleens and lymph nodes observed in tlr3(/) mice were accompanied by destruction of organ architecture and lymphocyte infiltration [3].
• In the presence of 4-1BB ligation and Toll-like receptor 3 (TLR)3 and/or TLR4 triggering, CD8 T cell clonal expansion and survival was augmented profoundly [13].
• Mast cells express TLR3 on the cell surface and intracellularly [4].

Associations of Tlr3 with chemical compounds

• Specifically, we show that mice of MOLF/Ei, Czech/Ei, and MSM/Ms strains are hypo-responsive to polyinosinic-polycytidylic acid (poly(I:C)) because of a mutation in Tlr3 [14].
• Double-stranded RNA (dsRNA) and its mimic, polyinosinic acid:polycytidylic acid [poly(I):poly(C)], are recognized by toll-like receptor 3 (TLR3) that induces the production of IFN-beta in many cell types [9].
• In contrast, the Toll-like receptor 3 agonist poly inosinic and cytidylic acid (polyI:C) had no effect on receptor expression [15].

Other interactions of Tlr3

• Immunostaining of nephritic kidney sections of autoimmune MRL(lpr/lpr) mice revealed TLR3 expression in infiltrating antigen-presenting cells as well as in glomerular mesangial cells [1].
• CONCLUSION: Arthritis triggered by dsRNA is not dependent on the expression of the dsRNA-signaling molecule PKR (or Toll-like receptor 3, as previously shown), but is associated with the ability to produce type I IFN and is critically dependent on type I IFN receptor signaling [16].
• Intranasal administration of HA vaccine with poly(I:C) up-regulated expression of Toll-like receptor 3 and alpha/beta interferons as well as Th1- and Th2-related cytokines [17].

Analytical, diagnostic and therapeutic context of Tlr3

• Tlr3-deficient (Tlr3(-/-)) mice were more resistant to lethal WNV infection and had impaired cytokine production and enhanced viral load in the periphery, whereas in the brain, viral load, inflammatory responses and neuropathology were reduced compared to wild-type mice [2].
• A clinical trial employing an immunotherapeutic approach based on the use of a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes carrying tumour-associated antigens is planned in advanced ovarian cancer in conjunction with conventional first line chemotherapy [18].

References