IL33 is a member of the IL-1 family and a ligand for the orphan receptor ST2 (also known as IL-1RL1). It plays a key role in innate and adaptive immunity, contributing to tissue homeostasis and responses to environmental stress. IL33 plays an important role in regulating infection and autoimmune diseases.

Cellular sources and cellular targets of IL33

IL33 is primarily released by endothelial cells, epithelial cells, and fibroblasts in response to tissue injury and/or mechanical stress . Once released, IL33 acts as an alarmin and activates various cell types, including Th2 cells, Tregs, basophils, mast cells, eosinophils, macrophages, dendritic cells, innate lymphoid cells (ILC2s), NK cells, and NKT cells. These cells respond to IL33 /ST2 signaling by producing pro- and anti-inflammatory mediators, depending on the immune context of different tissues and diseases.

(Data source: Xu H, et al. Mil Med Res. 2017)

IL33 structure:

The interleukin-33 (IL33) gene is located on the short arm of chromosome 9 at 9p24.1 and consists of 270 amino acids. Full-length IL33 contains two highly conserved domains: an N-terminal nuclear domain with nuclear localization and chromatin binding motifs and a C-terminal IL-1-like cytokine domain . IL33 possesses a conserved β-trefoil conformation and a central hydrophobic core composed of 12 β-sheets . Two ST2-binding sites have been identified in IL33. IL33 activates intracellular signaling pathways by binding to its specific primary receptor, ST2, and its co-receptor, IL-1 receptor accessory protein ( IL-1RAcP ). In this ternary complex, juxtaposition of the ST2 and IL-1RAcP cytoplasmic Toll/IL-1R ( TIR ) domains leads to activation of intracellular signaling pathways.

(Data source: Liew FY, et al. Nat Rev Immunol. 2016)

Function of IL33 in immune regulation:

IL33 is localized in the nucleus of expressing cells and becomes biologically active when released following cell injury or necrotic cell death. Binding of full-length or mature IL33 to ST2 and IL-1RAcP (a coreceptor for IL-1 superfamily members) leads to the binding of MyD88, IRAK1, and IRAK4 kinases to TRAF6, and activation of several MAP kinases and NF-κB.

IL33 binds to ST2, which is upregulated on activated CD8+ T cells, CD4+ Th1 cells, and NK cells, leading to enhanced proliferation and increased production of proinflammatory cytokines. Cells mediating type 2 immunity express ST2 and respond to IL33, proliferating and producing cytokines that support pathogen clearance and restoration of epithelial health. IL-13 production by ILC2s, CD4+ Th2 cells, Tregs, and basophils is crucial for generating reparative and regulatory macrophages that contribute to repair and support local Tregs.

(Data source: Dwyer GK, et al. Annu Rev Immunol. 2022)

IL33 and disease

IL33 plays a crucial role in regulating inflammatory responses and plays a pro-inflammatory role in inflammatory diseases such as sepsis and asthma. IL33 plays a pro-inflammatory role in sepsis by activating type 2 immune responses and enhancing immune cell function. It helps regulate the activity of neutrophils and ILC2s, promoting bacterial clearance at sites of infection and potentially influencing the severity and prognosis of sepsis.

(Data source: Zhou Y, et al. J Transl Med. 2023)

IL33 also plays an important role in chronic respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea (OSA). In these diseases, serum IL33 is elevated and is associated with the severity of the disease.

(Data source: Gabryelska A, et al. Front Immunol. 2019)

Targeted therapy strategies for IL33

Currently, there are many antibodies against IL33 and ST2 in clinical development for the treatment of COPD. Targeting strategies against IL33 and ST2 are of great significance in the treatment of the disease.

Anti-IL33 antibodies: By using monoclonal antibodies against IL33, the binding of IL33 to its receptor ST2 can be blocked, thereby inhibiting the IL33-mediated inflammatory response.

Anti-ST2 antibodies: Another strategy is to use anti-ST2 antibodies to block the ST2 receptor, which can reduce the activation of the IL33/ST2 signaling pathway and alleviate lung inflammation and airway hyperresponsiveness.

(Data source: Riera-Martínez L, et al. Int J Mol Sci. 2023)