Il17ra, encoding interleukin-17 receptor A, is a key component in the interleukin-17 signaling pathway. It serves as a common receptor for IL-17A and IL-17F, playing a significant role in various biological processes such as immune responses, inflammation regulation, and tissue homeostasis [5,6,8]. Dysregulation of the Il17ra-mediated signaling can lead to multiple disease conditions including autoimmunity, cancer, and osteoporosis [1,2,3,9,10]. Genetic models, especially gene knockout (KO) mouse models, have been crucial in deciphering its functions.

In pancreatic cancer, deletion of Il17ra from the pancreatic epithelial compartment, but not the hematopoietic compartment, led to delayed initiation and progression of premalignant lesions, along with increased infiltration of CD8+ cytotoxic T cells. This indicates that pancreatic epithelial Il17ra promotes tumorigenesis by reprogramming the immune landscape, partially through B7-H4 regulation [1]. In osteoporosis, the expression of Il17ra was significantly higher in patients compared to the normal group, suggesting its potential as a diagnostic marker, and functional enrichment analysis revealed its involvement in the disease through regulating local immune and inflammatory processes in bone tissue [2]. Polymorphisms in the Il17ra gene were identified as risk factors for developing Fanconi anemia, and were also associated with age and the presence of leukoplakia in Fanconi patients [3]. In a study on post-bronchiolitis outcomes, Il17ra gene variations showed no association with susceptibility to severe bronchiolitis in infancy, nor with post-bronchiolitis asthma or lung function at school age [4]. In ulcerative colitis, gingerenone A protected mice by directly interacting with Il17ra protein, inhibiting inflammatory signaling activation [7]. In pancreatic ductal adenocarcinoma (PDAC), Il17ra expressed by fibroblasts was required for IL-17A-producing CD8+ T cell-driven tumor growth, highlighting the crosstalk between T cells, fibroblasts, and tumor cells in PDAC progression [9]. In autoimmune-prone mice lacking Ets1, loss of Il17ra signaling led to enhanced autoimmunity, and combined with defective wound-healing-related γδ T-cell subset, increased susceptibility to skin staph infections [10].

In summary, Il17ra is essential in regulating immune responses and inflammation, with its dysregulation contributing to multiple disease states. The use of KO mouse models has significantly enhanced our understanding of Il17ra's role in pancreatic cancer, osteoporosis, Fanconi anemia, ulcerative colitis, PDAC, and autoimmune and infectious diseases, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Castro-Pando, Susana, Howell, Rian M, Li, Le, Moghaddam, Seyed J, McAllister, Florencia. . Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis. In Cancer immunology research, 12, 1170-1183. doi:10.1158/2326-6066.CIR-23-0527. https://pubmed.ncbi.nlm.nih.gov/38842383/

2. Deng, Ya-Jun, Li, Zhi, Wang, Bo, Zhang, Ying, Yuan, Bin. 2023. Immune-related gene IL17RA as a diagnostic marker in osteoporosis. In Frontiers in genetics, 14, 1219894. doi:10.3389/fgene.2023.1219894. https://pubmed.ncbi.nlm.nih.gov/37600656/

3. Mobile, Rafael Zancan, Mendes, Monalisa Castilho, Machado-Souza, Cleber, Torres-Pereira, Cassius Carvalho, Schussel, Juliana Lucena. 2023. IL17A and IL17RA gene polymorphisms in Fanconi anemia. In Brazilian oral research, 37, e012. doi:10.1590/1807-3107bor-2023.vol37.0012. https://pubmed.ncbi.nlm.nih.gov/36790253/

4. Lauhkonen, Eero, Holster, Annukka, Teräsjärvi, Johanna, He, Qiushui, Korppi, Matti. 2021. IL17RA variations showed no associations with post-bronchiolitis asthma or lung function. In Pediatrics international : official journal of the Japan Pediatric Society, 63, 196-201. doi:10.1111/ped.14387. https://pubmed.ncbi.nlm.nih.gov/32654355/

5. Gaffen, Sarah L, Jain, Renu, Garg, Abhishek V, Cua, Daniel J. . The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. In Nature reviews. Immunology, 14, 585-600. doi:10.1038/nri3707. https://pubmed.ncbi.nlm.nih.gov/25145755/

6. Nejman-Gryz, Patrycja, Paplińska-Goryca, Magdalena, Proboszcz, Małgorzata, Hermanowicz-Salamon, Joanna, Krenke, Rafal. 2021. The expression of IL17RA on sputum macrophages in asthma patients. In Cytokine, 143, 155518. doi:10.1016/j.cyto.2021.155518. https://pubmed.ncbi.nlm.nih.gov/33840588/

7. Liang, Jian, Dai, Weigang, Liu, Chuanghui, Wang, Wei, Tang, Hailin. 2024. Gingerenone A Attenuates Ulcerative Colitis via Targeting IL-17RA to Inhibit Inflammation and Restore Intestinal Barrier Function. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2400206. doi:10.1002/advs.202400206. https://pubmed.ncbi.nlm.nih.gov/38639442/

8. Brembilla, Nicolo Costantino, Senra, Luisa, Boehncke, Wolf-Henning. 2018. The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond. In Frontiers in immunology, 9, 1682. doi:10.3389/fimmu.2018.01682. https://pubmed.ncbi.nlm.nih.gov/30127781/

9. Picard, Felix Simon Ruben, Lutz, Veronika, Brichkina, Anna, Gaida, Matthias, Huber, Magdalena. 2023. IL-17A-producing CD8+ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts. In Gut, 72, 1510-1522. doi:10.1136/gutjnl-2022-327855. https://pubmed.ncbi.nlm.nih.gov/36759154/

10. Battaglia, Michael, Sunshine, Alex C, Luo, Wei, Wohlfert, Elizabeth, Garrett-Sinha, Lee Ann. 2023. Ets1 and IL17RA cooperate to regulate autoimmune responses and skin immunity to Staphylococcus aureus. In Frontiers in immunology, 14, 1208200. doi:10.3389/fimmu.2023.1208200. https://pubmed.ncbi.nlm.nih.gov/37691956/