Interleukin-33 (IL33), a cytokine belonging to the IL-1 family, is constitutively produced from structural and lining cells like fibroblasts, endothelial and epithelial cells [1,3,5]. Different from most cytokines, it is passively released during cell necrosis or tissue damage, acting as an alarmin to alert the immune system [1]. IL33 functions mainly through its receptor ST2, playing crucial roles in type-2 innate immunity by activating eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2s) [1]. It is involved in multiple biological processes and various diseases, such as allergic inflammation, cancer metastasis, and autoimmune diseases [1-3, 5-10].

In a mouse model of spontaneous breast cancer metastasis, targeting IL33 in vivo inhibited lung metastasis and attenuated immune cell recruitment and type 2 immunity, suggesting its role in facilitating breast cancer lung metastasis by modifying the immune microenvironment [2]. In pancreatic cancer, compartment-specific IL33 knockout mice showed that lack of stromal IL33 led to reprogramming of the tumor microenvironment, an increase in CD8+ T-cell infiltration and activation, and reduced tumor growth, indicating that CAF-derived IL33 in the pancreatic microenvironment promotes tumor growth [4].

In conclusion, IL33 is a key immune modulator with pleiotropic activities in immune responses and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases, as well as in cancer metastasis. Studies using IL33 KO/CKO mouse models have revealed its functions in breast and pancreatic cancer metastasis, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Chan, Ben C L, Lam, Christopher W K, Tam, Lai-Shan, Wong, Chun K. 2019. IL33: Roles in Allergic Inflammation and Therapeutic Perspectives. In Frontiers in immunology, 10, 364. doi:10.3389/fimmu.2019.00364. https://pubmed.ncbi.nlm.nih.gov/30886621/

2. Shani, Ophir, Vorobyov, Tatiana, Monteran, Lea, Barshack, Iris, Erez, Neta. 2020. Fibroblast-Derived IL33 Facilitates Breast Cancer Metastasis by Modifying the Immune Microenvironment and Driving Type 2 Immunity. In Cancer research, 80, 5317-5329. doi:10.1158/0008-5472.CAN-20-2116. https://pubmed.ncbi.nlm.nih.gov/33023944/

3. Tonacci, Alessandro, Quattrocchi, Paolina, Gangemi, Sebastiano. 2019. IL33/ST2 Axis in Diabetic Kidney Disease: A Literature Review. In Medicina (Kaunas, Lithuania), 55, . doi:10.3390/medicina55020050. https://pubmed.ncbi.nlm.nih.gov/30769901/

4. Donahue, Katelyn L, Watkoske, Hannah R, Kadiyala, Padma, Zhang, Yaqing, Pasca di Magliano, Marina. . Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth. In Cancer discovery, 14, 1964-1989. doi:10.1158/2159-8290.CD-24-0100. https://pubmed.ncbi.nlm.nih.gov/38958646/

5. 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/