Irf3-KO Mouse

Irf3, Interferon Regulatory Factor 3, is a key transcription factor in the interferon regulatory factor family. It plays a vital role in human innate antiviral immune responses, especially as a principal early regulator of type I interferons (TI-IFNs) downstream of intracellular virus sensing. The kinases IκB kinase epsilon (IKKε) and TANK-binding kinase-1 (TBK1), along with scaffold proteins, are believed to be part of an Irf3-activation complex. Understanding Irf3 is crucial for elucidating antiviral signaling pathways [1].

Genetic ablation of Irf3 in mice has revealed its diverse functions. In Irf3-deficient mice, they are hyper-susceptible to intestinal tumor development in AOM/DSS and Apcmin/+ models, as Irf3 normally inhibits the nuclear translocation of β-catenin to prevent aberrant Wnt signaling-mediated cell proliferation [2]. In myocardial infarction mouse models, genetic deficiency in Irf3 leads to impaired interferon-stimulated gene (ISG) expression but improved survival, indicating that Irf3 activation and type I IFN production fuel a fatal response [3]. In cholestasis-induced liver and kidney injury models, Irf3 knockout mice show attenuated tissue damage, fibrosis, and cell-death and inflammatory responses, suggesting bile acid-induced p-Irf3 and the Irf3-ZBP1 axis are central in pathogenesis [4]. In non-alcoholic fatty liver disease (NAFLD) mouse models, knocking down Irf3 reduces hepatocyte inflammation, apoptosis, and metabolic disorders [5]. In newly engineered conditional Irf3Δ/Δ mice and Irf3-deleted macrophages (Irf3MKO), respiratory virus infection leads to increased susceptibility, mortality, and enhanced inflammatory responses, showing that Irf3 in macrophages inhibits inflammatory signaling pathways to prevent viral pathogenesis [6].

In conclusion, Irf3 is essential in multiple biological processes. Through gene knockout and conditional knockout mouse models, it has been shown to be involved in tumorigenesis, responses to myocardial infarction, cholestatic liver and kidney injury, NAFLD, and viral pathogenesis. These models have provided valuable insights into the role of Irf3 in these disease areas, helping to understand its functions and potentially leading to new therapeutic strategies.

References:

1. Al Hamrashdi, Mariya, Brady, Gareth. 2022. Regulation of IRF3 activation in human antiviral signaling pathways. In Biochemical pharmacology, 200, 115026. doi:10.1016/j.bcp.2022.115026. https://pubmed.ncbi.nlm.nih.gov/35367198/

2. Tian, Miao, Wang, Xiumei, Sun, Jihong, Cai, Xiujun, Wang, Xiaojian. 2020. IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin. In Nature communications, 11, 5762. doi:10.1038/s41467-020-19627-7. https://pubmed.ncbi.nlm.nih.gov/33188184/

3. King, Kevin R, Aguirre, Aaron D, Ye, Yu-Xiang, Nahrendorf, Matthias, Weissleder, Ralph. 2017. IRF3 and type I interferons fuel a fatal response to myocardial infarction. In Nature medicine, 23, 1481-1487. doi:10.1038/nm.4428. https://pubmed.ncbi.nlm.nih.gov/29106401/

4. Zhuang, Yuan, Ortega-Ribera, Martí, Thevkar Nagesh, Prashanth, Parikh, Samir M, Szabo, Gyongyi. 2023. Bile acid-induced IRF3 phosphorylation mediates cell death, inflammatory responses, and fibrosis in cholestasis-induced liver and kidney injury via regulation of ZBP1. In Hepatology (Baltimore, Md.), 79, 752-767. doi:10.1097/HEP.0000000000000611. https://pubmed.ncbi.nlm.nih.gov/37725754/

5. Qiao, J T, Cui, C, Qing, L, Hou, X G, Chen, L. 2017. Activation of the STING-IRF3 pathway promotes hepatocyte inflammation, apoptosis and induces metabolic disorders in nonalcoholic fatty liver disease. In Metabolism: clinical and experimental, 81, 13-24. doi:10.1016/j.metabol.2017.09.010. https://pubmed.ncbi.nlm.nih.gov/29106945/

6. Chakravarty, Sukanya, Varghese, Merina, Fan, Shumin, Chakravarti, Ritu, Chattopadhyay, Saurabh. 2024. IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis. In Science advances, 10, eadn2858. doi:10.1126/sciadv.adn2858. https://pubmed.ncbi.nlm.nih.gov/39121222/