Irf3, the interferon regulatory factor 3, is a key transcription factor in the innate antiviral immune responses, playing a vital role in the production of type I interferons (TI-IFNs) downstream of intracellular virus sensing. It is involved in multiple signaling pathways, such as those related to the kinases IκB kinase epsilon (IKKε) and TANK-binding kinase-1 (TBK1), and scaffold proteins like TRAF family member-associated NF-κB activator (TANK), NF-κB-activating kinase-associated protein 1 (NAP1) and TANK-binding kinase 1-binding protein 1 (TBKBP1)/similar to NAP1 TBK1 adaptor (SINTBAD) [1].

In gene knockout studies, Irf3-deficient mice have provided crucial insights. In colorectal cancer research, Irf3-deficient mice showed hyper-susceptibility to intestinal tumor development in AOM/DSS and Apcmin/+ models, as genetic ablation of Irf3 promoted intestinal epithelial cell proliferation via aberrantly activating Wnt signaling [2]. In myocardial infarction, Irf3-deficient mice had impaired interferon-stimulated gene (ISG) expression, decreased cardiac expression of inflammatory cytokines and chemokines, reduced inflammatory cell infiltration, and improved survival compared to controls [3]. In cholestasis-induced liver and kidney injury, Irf3 knockout (Irf3-/-) mice had significantly attenuated liver and kidney damage and fibrosis, with cell-death pathways and inflammatory responses being significantly reduced [4]. In non-alcoholic fatty liver disease, knocking down Irf3 in a high-fat diet-induced obese mouse model led to a reduction in free fatty acid (FFA)-induced hepatic inflammation and apoptosis, enhanced glycogen storage, and alleviated lipid accumulation [5]. In respiratory virus infection, conditional Irf3Δ/Δ mice (engineered for conditional knockout) showed increased susceptibility and mortality, along with enhanced inflammatory gene expression, lung inflammation, and immunopathology, with deletion of Irf3 in macrophages (Irf3MKO) mimicking these effects [6].

In conclusion, Irf3 is essential in regulating innate antiviral immunity, and its role extends to preventing tumorigenesis, modulating responses to myocardial infarction, cholestasis-induced organ injury, non-alcoholic fatty liver disease, and viral-induced inflammation. Gene knockout and conditional knockout mouse models have been instrumental in revealing these functions across various disease areas, deepening our understanding of its role in biological processes and potential as a therapeutic target.

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/