IL-33/ST2 Signaling Axis

Canonical source: Reactome R-HSA-9660821

Pathway Overview

The IL-33/ST2 signaling axis is a critical epithelial-derived alarmin pathway that bridges innate and adaptive immunity. IL-33, constitutively expressed in epithelial barrier tissues, is released upon cellular damage or necrosis. It binds the ST2 receptor (encoded by IL1RL1) on type 2 innate lymphoid cells (ILC2s), mast cells, and Th2 cells, driving production of type 2 cytokines (IL-5, IL-13) that orchestrate eosinophilic inflammation, mucus hypersecretion, and airway remodeling. This pathway represents a key node where environmental exposures (particularly PM2.5) converge with genetic susceptibility to amplify allergic airway disease.

Environmental Triggers

ExposureTrigger type
air-pollutionOxidative epithelial damage releases IL-33
endotoxinMicrobial pattern recognition triggers epithelial alarmin release
tobaccoCigarette smoke-induced epithelial necrosis

Genetic Modulation Points

Key genes

  • il33— Ligand; epithelial alarmin released upon damage
  • il1rl1— ST2 receptor; primary receptor for IL-33 on ILC2s, mast cells, and Th2 cells
  • tslp— Co-alarmin amplifying epithelial danger signaling
  • hla-drb1— Antigen presentation modulating downstream adaptive immune response

Regulatory checkpoints

  • IL-33 release— ORMDL3, GSDMBTherapeutic target
  • ST2 receptor— IL1RL1Therapeutic target

Tissue Specificity

bronchial epithelium— Primary IL-33 source
type 2 innate lymphoid cells— Primary responder
airway smooth muscle— Downstream remodeling

Disease Relevance

Linked diseases

  • asthma— IL-33/ST2 drives eosinophilic airway inflammation and airway hyperresponsiveness
  • atopic-dermatitis— Skin barrier-driven IL-33 release activates cutaneous ILC2s

Linked exposures

  • air-pollution— PM2.5 oxidative damage triggers IL-33 release from bronchial epithelium
  • tobacco-smoke-prenatal— Prenatal tobacco smoke exposure may prime IL-33 axis in developing airways

Pathway Diagram

Pathway diagram placeholder. A visual representation of this pathway will be integrated when available.

Evidence Nodes

Evidence for this pathway is derived from:

  • 3 environmental trigger(s)
  • 4 key gene(s)
  • 2 linked disease(s)
  • 2 linked exposure(s)

References

  1. 1.Cayrol C, Girard JP (2014). IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Current Opinion in Immunology. doi:10.1016/j.coi.2013.11.010
  2. 2.Moffatt MF, et al. (2010). A large-scale, consortium-based genomewide association study of asthma. New England Journal of Medicine. doi:10.1056/NEJMoa0906312
  3. 3.Torgerson DG, et al. (2011). Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nature Genetics. doi:10.1038/ng.888
  4. 4.Ober C, Yao TC (2011). Gene–environment interactions in human diseases. Immunological Reviews. doi:10.1111/j.1600-065X.2011.01029.x
  5. 5.Schmitz J, et al. (2005). IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. doi:10.1016/j.immuni.2005.09.015