Il1rl1, also known as ST2, encodes the receptor for interleukin-33 (IL-33). IL-33/Il1rl1 signaling is involved in various immune-related pathways, playing a crucial role in immune responses, especially in type-2, type-1 and regulatory immune responses. It is implicated in numerous biological processes including fibrosis, cell survival, and is associated with many diseases such as asthma, allergic rhinitis, and leukemia [1,2,3,4,5,6]. Genetic models, like knockout (KO) mouse models, are valuable tools for studying its functions.

In a Cbfb-MYH11 knock-in mouse model, Il1rl1 was found to be dynamically expressed on leukemia stem cells. Treatment with IL-33 increased serial replating ability and expression of pro-survival proteins in vitro, and Il1rl1+ cells survived chemotherapy better than Il1rl1-cells in vivo, indicating that Il1rl1 promotes the survival of Cbfb-MYH11+ leukemia cells [3]. In another study, in the context of tumor microenvironment, blocking Il1rl1 signaling in regulatory T (Treg) cells enhanced the antitumor activity of IL-33 and PD-1 blockade, suggesting its role in impeding antitumor immunity [1].

In conclusion, Il1rl1 is a key receptor in the IL-33 signaling pathway with significant functions in immune-related processes and disease development. Mouse models, such as the Cbfb-MYH11 knock-in mouse, have been instrumental in revealing its role in leukemia cell survival and tumor immune tolerance, providing insights into potential therapeutic targets for leukemia and cancer immunotherapy.

References:

1. Sun, Runzi, Zhao, Hongyu, Gao, David Shihong, Chen, Kong, Lu, Binfeng. 2023. Amphiregulin couples IL1RL1+ regulatory T cells and cancer-associated fibroblasts to impede antitumor immunity. In Science advances, 9, eadd7399. doi:10.1126/sciadv.add7399. https://pubmed.ncbi.nlm.nih.gov/37611111/

2. Sunata, Keeya, Miyata, Jun, Kawashima, Yusuke, Arita, Makoto, Fukunaga, Koichi. 2024. Multiomics analysis identified IL-4-induced IL1RL1high eosinophils characterized by prominent cysteinyl leukotriene metabolism. In The Journal of allergy and clinical immunology, 154, 1277-1288. doi:10.1016/j.jaci.2024.07.012. https://pubmed.ncbi.nlm.nih.gov/39067484/

3. Wang, Yiqian, Richter, Lisa, Becker, Michelle, Amador, Catalina, Hyde, R Katherine. 2019. IL1RL1 is dynamically expressed on Cbfb-MYH11+ leukemia stem cells and promotes cell survival. In Scientific reports, 9, 1729. doi:10.1038/s41598-018-38408-3. https://pubmed.ncbi.nlm.nih.gov/30742053/

4. Cayrol, Corinne, Girard, Jean-Philippe. . Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. In Immunological reviews, 281, 154-168. doi:10.1111/imr.12619. https://pubmed.ncbi.nlm.nih.gov/29247993/

5. Ranjbar, Maral, Matloubi, Mojdeh, Sadegh, Shaghayegh, Janani, Leila, Assarehzadegan, Mohammad-Ali. 2021. IL1RL1 single nucleotide polymorphisms are associated with asthma in the Iranian population. In Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, 92, . doi:10.4081/monaldi.2021.1697. https://pubmed.ncbi.nlm.nih.gov/34964571/

6. Li, Zhengqing, Ren, Jiajia, Zhang, Jirong, Liu, Yonglin, Wang, Qiang. 2022. Association between IL1RL1 gene polymorphisms and allergic rhinitis risk in the Chinese Han population. In Journal of clinical laboratory analysis, 36, e24747. doi:10.1002/jcla.24747. https://pubmed.ncbi.nlm.nih.gov/36310516/