IL-33 Cytokine Biology in Inflammatory Disorders

Interleukin-33 (IL-33) is a dual-function cytokine predominantly expressed in the nuclei of epithelial, endothelial and stromal cells. Upon cell stress or injury, IL-33 is released as an alarmin to engage its cognate receptor ST2 (also known as IL-1RL1) on a range of immune cells. This engagement triggers MyD88-dependent signalling cascades, activating NF-κB and MAP kinases, and driving context-dependent immune responses. IL-33–ST2 signalling is central to type-2 immunity, promoting Th2 cells, eosinophils, mast cells and group 2 innate lymphoid cells (ILC2s), but it also modulates type-1 and regulatory T-cell responses. Cleavage by proteases such as neutrophil elastase or cathepsin G can generate more bioactive forms of IL-33, amplifying its inflammatory potential. Dysregulated IL-33 activity has been implicated in allergic asthma, atopic dermatitis, cardiac remodelling, organ fibrosis and metabolic disease. Recent work has refined our understanding of transcriptional, structural and post-translational checkpoints that govern IL-33 availability and function, highlighting opportunities for targeted modulation in diverse inflammatory disorders.

Research from Nature Portfolio

Recent studies have uncovered a lineage-specific promoter that drives ST2 expression in type-1 T cells, revealing how alternative transcriptional control tailors IL-33 responsiveness during antiviral immunity. Loss of this promoter selectively impairs ST2 expression on cytotoxic and T-helper 1 cells, resulting in reduced expansion of effector CD8+ T cells upon viral challenge. This discovery offers a blueprint for cell-subset–specific targeting of IL-33–ST2 signalling. In parallel, structural analyses have elucidated how a helminth-derived effector protein, HpARI2, binds directly to IL-33 and sterically blocks the binding surface for ST2. Crystallographic data show that HpARI2’s CCP-like domains compete with ST2, preventing complex formation and downstream immune activation. These insights into receptor antagonism provide templates for novel biologics that mimic parasite-mediated suppression of IL-33-driven pathology.

IL-33 Cytokine Biology in Inflammatory Disorders publication trend

The graph below shows the total number of articles in il-33 cytokine biology in inflammatory disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Alarmin: An endogenous molecule released upon tissue damage that alerts the immune system to injury or infection.

ST2 (IL-1RL1): The membrane-bound receptor for IL-33, whose activation initiates MyD88-dependent inflammatory signalling.

Group 2 innate lymphoid cells (ILC2s): A subset of innate lymphoid cells that produce type-2 cytokines in response to IL-33 and contribute to allergic inflammation.

Protease cleavage: Post-translational processing by enzymes such as elastase, which generates more active forms of IL-33 from its precursor.

References

1. A type 1 immunity-restricted promoter of the IL−33 receptor gene directs antiviral T-cell responses. Nature Immunology (2024).
2. Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI2. Nature Communications (2024).
3. A neutrophil elastase-generated mature form of IL-33 is a potent regulator of endothelial cell activation and proliferative retinopathy. Experimental & Molecular Medicine (2024).
4. Partial reduction of interleukin‐33 signaling improves senescence and renal injury in diabetic nephropathy. MedComm (2024).
5. Interleukin‐33 (IL‐33): A nuclear cytokine from the IL‐1 family. Immunological Reviews (2017).
6. The IL-1-Like Cytokine IL-33 Is Constitutively Expressed in the Nucleus of Endothelial Cells and Epithelial Cells In Vivo: A Novel ‘Alarmin’?. PLOS ONE (2008).
7. The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases. Frontiers in Immunology (2017).
8. Role of IL-33 in inflammation and disease. Journal of Inflammation (2011).
9. Interleukin-33 Ameliorates Experimental Colitis through Promoting Th2/Foxp3+ Regulatory T-Cell Responses in Mice. Molecular Medicine (2012).
10. IL33: Roles in Allergic Inflammation and Therapeutic Perspectives. Frontiers in Immunology (2019).
11. IL-33/ST2 Axis in Organ Fibrosis. Frontiers in Immunology (2018).