IL-33 family members and asthma - bridging innate and adaptive immune responses

Abstract

The discovery of IL-33 as the ligand for the orphan Th2 associated receptor ST2 has uncovered a whole range of different avenues for this pathway. Although the extracellular functions of ST2 as a marker for Th2 cell and mast cell activity were well defined, the complexities of IL-33 regulation, nuclear function and secretion are only just being realised. The well documented expression pattern of ST2 has identified a role for the IL-33/ST2 axis in the classical Th2 cell and mast cell driven pathogenesis of asthma and anaphylaxis. However, the induction of IL-33 expression by environmental or endogenous triggers now suggests a wider role for the pathway during infection, inflammation and tissue damage.

Figure 1

IL-33 signalling pathways. IL-33 mediates its function by binding to a receptor complex comprising ST2 and IL-1 receptor accessory protein (IL-1RAP) leading to the recruitment of the myeloid differentiation primary-response protein 88 (MYD88) complex. Although the mechanism is unclear, the complex is thought to activate at least two independent pathways involving the mitogen activated protein kinase (MAPK) pathway as well as the phospholipase D (PLD)-sphingosine kinase (SPHK) pathway, ultimately leading to activation of MAP kinases and NFκB. SIGIRR acts as a negative regulator for signalling, and soluble ST can bind directly to IL-33 thus acting as a decoy receptor. Although biologically active IL-33 is generated passively by necrotic cells, caspase cleavage during apoptosis leads to inactivation.

Figure 2

Leukocyte expression of ST2 and effect of interaction with IL-33. ST2 is expressed on a number of leukocytes involved in the asthmatic response and binding of IL-33 results in a wide variety of effects that influence the course of allergic reactions.

Figure 3

IL-33 in asthma. Exposure to airborne allergens, pollution, respiratory viruses causes damage to the pulmonary epithelium and/or activation of pattern recognition receptors such as TLRs leading to the release of IL-33 from lung structural cells such as epithelial cells. IL-33 likely drives allergen sensitisation via effects on airway dendritic cells and development of Th2 mediated pathology via generation of IL-4, IL-5 and IL-13. IL-33 leads to the generation of macrophages with an alternatively activated phenotype and to the recruitment, maturation and survival of eosinophils. Importantly, IL-33 is able to induce airway hyperresponsiveness via mast cells and IL-13.