Il22ra1, the interleukin 22 receptor subunit alpha 1, is a crucial component in the IL-22 signaling pathway. IL-22, a cytokine of the IL-10 family, binds to Il22ra1, initiating signaling cascades such as the JAK/STAT pathway, which is involved in immunity, tissue homeostasis, and cancer development [2,3]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in understanding its functions.

In hepatocyte-specific Il22ra1 knockout mice, hepatic steatosis, insulin resistance, and inflammation occur due to increased lipogenesis from the accumulation of hepatic oxysterols, revealing its role in maintaining hepatic lipid homeostasis [1]. In pancreatic cancer, high Il22ra1 expression in cancer cells is associated with poor prognosis, and IL-22 promotes cancer stemness via the Il22ra1/STAT3 signaling in the IL22RA1hi population, which has high stemness potential and tumorigenicity [3]. Intestinal epithelium-specific Il22ra1 knockout mice show that Il22ra1 signaling in the intestine is important for regulating systemic glucose metabolism and alleviating obesity-associated disorders [4]. In acute kidney injury, knocking out Il22ra1 specifically in kidney tubule cells reduces DNA damage response activation, cell death, and kidney injury [5].

In summary, Il22ra1 plays essential roles in multiple biological processes and disease conditions. KO and CKO mouse models have demonstrated its significance in hepatic lipid regulation, cancer development, glucose and lipid metabolism, and acute kidney injury. Understanding Il22ra1's functions provides insights into the mechanisms of these diseases and potential therapeutic targets.

References:

1. Huang, Yeping, Yu, Fan, Ding, Yue, Lu, Yan, Hu, Cheng. 2024. Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver. In Hepatology (Baltimore, Md.), 81, 1564-1582. doi:10.1097/HEP.0000000000000998. https://pubmed.ncbi.nlm.nih.gov/38985984/

2. Zhang, Shuai, Yang, Guiyan. 2022. IL22RA1/JAK/STAT Signaling Acts As a Cancer Target Through Pan-Cancer Analysis. In Frontiers in immunology, 13, 915246. doi:10.3389/fimmu.2022.915246. https://pubmed.ncbi.nlm.nih.gov/35874683/

3. He, Weizhi, Wu, Jinghua, Shi, Juanjuan, Sun, Yong-Wei, Xue, Jing. 2018. IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer. In Cancer research, 78, 3293-3305. doi:10.1158/0008-5472.CAN-17-3131. https://pubmed.ncbi.nlm.nih.gov/29572224/

4. Gaudino, Stephen J, Singh, Ankita, Huang, Huakang, Morgun, Andrey, Kumar, Pawan. 2024. Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders. In Nature communications, 15, 1597. doi:10.1038/s41467-024-45568-6. https://pubmed.ncbi.nlm.nih.gov/38383607/

5. Taguchi, Kensei, Sugahara, Sho, Elias, Bertha C, Canaud, Guillaume, Brooks, Craig R. 2023. IL-22 is secreted by proximal tubule cells and regulates DNA damage response and cell death in acute kidney injury. In Kidney international, 105, 99-114. doi:10.1016/j.kint.2023.09.020. https://pubmed.ncbi.nlm.nih.gov/38054920/