Interleukin-1 receptor associated kinase 3 (IRAK3), a cytoplasmic homeostatic mediator of inflammatory responses, is a key player in the innate immune system. It inhibits signalling cascades downstream of myddosome complexes associated with toll like receptors [1]. IRAK3 contains a death domain, a pseudokinase domain with a guanylate cyclase centre, and a C-terminus domain interacting with tumour necrosis factor receptor associated factor 6 (TRAF6) [1]. It is associated with many inflammatory diseases, such as sepsis, and is involved in endotoxin tolerance to maintain inflammatory homeostasis [5].

In acute pancreatitis, deletion of IRAK3 in Irak3-/- mice enhanced the migration of CCR2+ monocytes into the pancreas and triggered a pro-inflammatory type 1 immune response [2]. In a mild AP model, this enhanced pro-inflammatory response decreased pancreatic damage, while in a severe AP model, it led to a severe systemic inflammatory response syndrome (SIRS) and increased local and systemic damage [2]. In monocyte-derived dendritic cells, Nuclease technology-mediated knockout of IRAK3 increased IL-12 production upon lipopolysaccharide (LPS) stimulation [3]. In zebrafish, two IRAK3 variants were discovered, with IRAK3a acting as a pathway enhancer and IRAK3b playing a negative role, and both inhibiting the activity of IRAK1/4 [4].

In summary, IRAK3 is crucial in modulating inflammatory responses and innate immunity. Studies using gene knockout models, such as Irak3-/- mice in acute pancreatitis research and Nuclease technology-mediated knockout in dendritic cells, have revealed its role in specific disease conditions. These models contribute to understanding how IRAK3 affects the progression of inflammatory diseases, offering potential insights for treatment strategies.

References:

1. Freihat, L A, Wheeler, J I, Wong, A, Manallack, D T, Irving, H R. 2019. IRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity. In Scientific reports, 9, 15468. doi:10.1038/s41598-019-51913-3. https://pubmed.ncbi.nlm.nih.gov/31664109/

2. Thiel, Franziska G, Asgarbeik, Saeedeh, Glaubitz, Juliane, Weiss, Frank Ulrich, Sendler, Matthias. 2023. IRAK3-mediated suppression of pro-inflammatory MyD88/IRAK signaling affects disease severity in acute pancreatitis. In Scientific reports, 13, 10833. doi:10.1038/s41598-023-37930-3. https://pubmed.ncbi.nlm.nih.gov/37402858/

3. Rowley, Ann, Brown, Brian S, Stofega, Mary, Rivkin, Alexey, Woller, Kevin R. 2022. Targeting IRAK3 for Degradation to Enhance IL-12 Pro-inflammatory Cytokine Production. In ACS chemical biology, 17, 1315-1320. doi:10.1021/acschembio.2c00037. https://pubmed.ncbi.nlm.nih.gov/35580266/

4. Weng, Panwei, Lan, Mengjiao, Zhang, Hao, Xu, Anlong, Huang, Shengfeng. . Both IRAK3 and IRAK1 Activate the MyD88-TRAF6 Pathway in Zebrafish. In Journal of immunology (Baltimore, Md. : 1950), 213, 362-372. doi:10.4049/jimmunol.2400054. https://pubmed.ncbi.nlm.nih.gov/38847613/

5. Nguyen, Trang Hong, Turek, Ilona, Meehan-Andrews, Terri, Zacharias, Anita, Irving, Helen. 2020. Analysis of interleukin-1 receptor associated kinase-3 (IRAK3) function in modulating expression of inflammatory markers in cell culture models: A systematic review and meta-analysis. In PloS one, 15, e0244570. doi:10.1371/journal.pone.0244570. https://pubmed.ncbi.nlm.nih.gov/33382782/