Tlr3, Toll-like receptor 3, is a member of the TLR family. It is a crucial RNA sensor that mediates the transcriptional induction of type I interferons (IFNs), pro-inflammatory cytokines, and chemokines, establishing an antiviral host response. Unlike other TLR family members, TLR3 is utterly dependent on the Toll-interleukin-1 receptor (TIR)-domain-containing adaptor-inducing IFN-β (TRIF) [1].

In the context of disease, TLR3-deficient mice show reduced lung metastasis in spontaneous metastatic models, indicating that lung epithelial cell TLR3 activation by tumor exosomal RNAs is crucial for neutrophil recruitment and lung metastatic niche formation [3]. In chronic neuropathic pain in mice, compared to wild-type (WT) mice, TLR3 knockout (KO) mice and TLR3-specific neuronal knockdown mice display improved cognitive function, reduced levels of inflammatory cytokines and neuronal apoptosis, and attenuated injury to hippocampal neuroplasticity, suggesting that extracellular RNAs-TLR3 signaling contributes to cognitive impairment [2]. Also, TLR3 deficiency in mice infected with Clonorchis sinensis causes severe clonorchiasis with increased parasite burden, exacerbated pro-inflammatory cytokine expression, and liver fibrosis, while Poly (I:C) intervention (which activates TLR3) alleviates these symptoms [4].

In conclusion, Tlr3 plays essential roles in antiviral innate immune responses, cancer metastasis, cognitive function after chronic neuropathic pain, and liver fibrosis caused by Clonorchis sinensis infection. Studies using TLR3 KO mouse models have been instrumental in revealing these functions, contributing to a better understanding of the underlying mechanisms in these disease areas.

References:

1. Chen, Yujuan, Lin, Junhong, Zhao, Yao, Ma, Xianping, Yi, Huashan. . Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses. In Journal of Zhejiang University. Science. B, 22, 609-632. doi:10.1631/jzus.B2000808. https://pubmed.ncbi.nlm.nih.gov/34414698/

2. Zhang, Xueying, Gao, Rui, Zhang, Changteng, Zhu, Tao, Chen, Chan. 2023. Extracellular RNAs-TLR3 signaling contributes to cognitive impairment after chronic neuropathic pain in mice. In Signal transduction and targeted therapy, 8, 292. doi:10.1038/s41392-023-01543-z. https://pubmed.ncbi.nlm.nih.gov/37544956/

3. Liu, Yanfang, Gu, Yan, Han, Yanmei, Zheng, Jianming, Cao, Xuetao. . Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils. In Cancer cell, 30, 243-256. doi:10.1016/j.ccell.2016.06.021. https://pubmed.ncbi.nlm.nih.gov/27505671/

4. Wang, Yuru, Gong, Pengtao, Zhang, Xuancheng, Li, Xin, Li, Jianhua. 2023. TLR3 activation by Clonorchis sinensis infection alleviates the fluke-induced liver fibrosis. In PLoS neglected tropical diseases, 17, e0011325. doi:10.1371/journal.pntd.0011325. https://pubmed.ncbi.nlm.nih.gov/37167198/