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

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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.

Introduction

IL-33 and its receptor are part of the IL-1 family, and their interactions promote a variety of actions from a number of different cell types. Unique within the IL-1 family, IL-33 is associated with the promotion of systemic Th2 responses. The IL-33/ST2 axis is thought to be intimately involved in the promotion and maintenance of allergic inflammation via a number of cell types that include Th2 cells, mast cells and basophils, and structural cells such as airway epithelium and smooth muscle cells. Although first identified as a protein expressed by lymph node-associated endothelial cells bioinformatic analysis identified IL-33 as the ligand for the former orphan receptor ST2 [1]. IL-33 binds a heterodimeric receptor complex consisting of ST2 and the ubiquitously expressed IL-1R accessory protein (IL-1R-AP) which promotes signalling via the TIR domain of IL-1RAP and activates several signalling proteins including, NFkB and mitogen activated protein (MAP) kinases such as p38 and JNK [2, 3] (Figure 1). This signalling cascade distinguishes IL-33 from the classical Th2 type cytokines which signal through JAK-STAT pathways. ST2 (also known as IL1RL1, T1, DER-4, Fit-1 or IL1R4) is a member of the TLR/IL-1R (TIR) family, and has 38% amino acid homology to the IL-1R. Due to differential splicing the ST2 gene encodes at least three isoforms of protein, a soluble form (sST2), a membrane bound form (ST2L) and a variant ST2 [4]. ST2 gene expression is widespread but the membrane bound form is most highly expressed on mast cells and T helper (Th2) cells [5, 6]. This led to the association between the ST2/IL-33 axis and Th2 type pathologies such as asthma. More recent analysis has determined that IL-33 interacting with ST2 on a range of different leukocytes promotes a number of key inflammatory pathways that have the potential to initiate and propagate allergic inflammation [3].

Section snippets

IL-33 signalling

IL-33 localises to the nucleus of resting cells and binds chromatin via H2A–H2B histone complex, exerting a potential transcriptional repressor effect [7]. How it migrates from this nuclear localization for interaction with its extracellular receptor, ST2, is less clear. IL-33 lacks a specific signal peptide to enable it to be processed for secretion via the ER-Golgi pathway. Caspase-1 cleavage of pro-IL-33 has been reported in vitro, although IL-33 lacks a classical caspase-1 cleavage site.

Regulation of IL-33 activity

The secretion capabilities of IL-33 have the potential to drive harmful inflammation, thus mechanisms have evolved to regulate IL-33 functions in vivo. A soluble form of the IL-33R, termed sST2, is able to sequester and neutralise IL-33. This sST2 develops as an alternatively spliced mRNA induced by serum as well as anti-inflammatory signals such as vitamin D. sST2 shares a common extracellular domain with ST2 but lacks the transmembrane and intracellular Toll-interleukin-1R domains [12].

Expression of ST2 on leukocytes involved in the asthmatic response

ST2 is expressed on Th2 cells and IL-33 is able to influence Th2 function in vitro and in vivo (Figure 2). IL-33 promotes secretion of the Th2 cytokines IL-5 and IL-13 from Th2 cells derived from allergic donors after TCR-dependent or independent stimulation [16]. Interestingly, substantial amounts of IFNγ were also produced. In the presence of allergen, IL-33 is able to polarise mouse or human naive CD4+ T cells into a population of T cells that produce mainly IL-5 but not IL-4 [17•]. This

Expression of IL-33 in the lung

Constitutive expression of IL-33 has been determined in a number of tissues, primarily stromal cells, including fibroblasts, cardiomyocytes, keratinocytes, adipocytes and epithelial cells at mucosal surfaces [33]. A recent study used a combination of tissue microarrays and antibody staining and showed widespread expression of IL-33 in the endothelial cells of large and small vessels in most normal human tissues, as well as tumours [11]. Constitutive nuclear expression of IL-33 was also observed

IL-33/ST2 interactions drive allergic pathology in vivo

Evidence that IL-33/ST2 interactions are functionally important in allergic inflammation comes from mouse model studies which have manipulated ligand/receptor interactions. Administration of blocking anti-ST2 antibodies or ST2-Ig fusion protein to allergic mice abrogated Th2 cytokine production in vivo, eosinophilic pulmonary inflammation and AHR but had no effect on Th1 driven airway inflammation [5]. Similarly, anti-IL-33 antibodies ameliorated eosinophil recruitment, Th2 cytokine production,

IL-33 and heterogeneity of asthma phenotypes

Asthma has classically been viewed as a Th2 mediated disease with therapeutic efforts directed towards blocking Th2 cytokines and preventing eosinophil recruitment and survival. However, this view is rapidly changing with the realisation that distinct clinical phenotypes of asthma exist coupled with the fact that results from trials targeting the Th2 response have been underwhelming [45]. A central role for the pulmonary epithelium in directing and propagating allergic responses has been

SNPS in asthma

Genetic evidence is accumulating to increase the association between IL-33/ST2 and development of asthma. IL-33 levels have been shown to be increased in severe asthma [35] as well as patients with allergic pollinosis [47] and in atopic patients with anaphylaxis [48]. Genetic analysis has linked polymorphisms in the IL-33 and ST2 genes with asthma and allergy-related traits [2]. Single nucleotide polymorphisms (SNPs) in the IL-33 gene have been associated with asthma, eosinophils and also

Conclusions

IL-33 is a central player in the development of allergic inflammation. Although the expression pattern of its receptor, ST2 implicated an association in generating type 2 immune reactions some of the novel functions assigned to this receptor/ligand axis indicate an expanding role. The fact that IL-33 is able to function as an ‘alarmin’ and will be secreted following tissue damage is important in the context of the lung. The pulmonary epithelium is prone to damage from pathogens such as viruses,

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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