Mini reviewThe IL-33/ST2 axis: Role in health and disease
Introduction
Interleukin-33 (IL-33), a member of the IL1 cytokine family, is mainly associated with the induction of T-helper type 2 (Th2) immune response through its receptor, ST2 [1]. Several immune cell types express IL-33, such as macrophages and dendritic cells, as do non-immune cells, such as endothelial cells, epithelial cells and fibroblasts [1], [2], [3], [4]. IL33 was initially described as a nuclear repressor factor, and later identified as an extracellular ligand for ST2 [1], [2]. The ST2 receptor, encoded by the IL1RL1 gene, is expressed as a ST2L membrane-anchored receptor variant activated by IL-33, and as the soluble variant sST2, which acts as a decoy receptor and has anti-inflammatory properties [5], [6].
The IL-33/ST2 axis has been implicated in numerous disease states, including asthma, rheumatoid arthritis and inflammatory bowel diseases [6], [7], [8] and, more recently, in cancer and Alzheimer’s disease [9], [10].
Here, we review the role of IL-33/ST2 system in innate and adaptive immunity and discuss its impact on inflammatory disorders.
Section snippets
The dual role of IL-33: a damage-associated molecular pattern (DAMP) and a cytokine
IL-33 was identified in 2003 as a nuclear protein highly expressed in high endothelial venules (HEV) and initially named nuclear factor from HEV (NF-HEV) [2]. Full-length human IL-33 protein has 270 amino acids and contains a homeodomain-like helix-turn-helix in its N-terminus, important for nuclear localization, heterochromatin association and transcriptional repressor activities [2], [11]. On the other hand, full-length IL-33 can, through its N-terminal domain (amino acids 66–109), can
Expression of ST2 isoforms
The ST2 receptor is a type-1 transmembrane protein encoded by the IL1RL1 gene [5]. ST2 was considered an “orphan” receptor for many years, lacking a specific ligand, until its association with IL-33 was demonstrated [1].
Four ST2 isoforms are generated by alternative splicing (Table 1) (Fig. 1B). These comprise ST2L, corresponding to a membrane-anchored receptor, which is highly homologous to IL-1 type-1 receptors, with extracellular, transmembrane and cytoplasmic domains [20], [21]; sST2, a
IL-33/ST2 signaling
IL-33 can induce different inflammatory responses depending on the cell type (Fig. 2). Unlike Th1 cells, Th2 cells express ST2L, and exposure to IL-33 induces IL-5 and IL-13 secretion [1], [38]. Mast cells treated with IL-33 produce IL-4, IL-5 and IL-6 [39], while primary keratinocytes exposed to IL-33 secrete pro-inflammatory cytokines, such as IL-6 and TNF-α [40]. IL-33 recognition by ST2L promotes receptor dimerization with the IL-1 receptor-accessory protein (IL-1RAcP) which is required as
Airway disorders: asthma and allergy
IL-33 is basally expressed in mouse lung tissue and human small airway epithelial cells, lung fibroblast or bronchial smooth muscle cells [1], [28]. There is evidence for higher levels of IL-33 in epithelial cells, airway smooth muscle cells and serum of patients with asthma or allergy compared with healthy controls [57], [58], [59].
Mice treated intranasally with IL-33 alone show airway hyper responsiveness, characterized by elevated eosinophil and monocyte numbers in bronchoalveolar lavage
Conclusions
The IL-33/ST2 signaling has emerged as a pathway with a central role in processes of the immune response, homeostasis and tissue injury/repair. IL-33 exerts different functions depending on subcellular localization, proteolytic cleavage and cell target. Furthermore, the IL-33/ST2 system has been linked with various immune-associated disorders, including inflammatory diseases with a Th-1 or Th-2 profile, cardiovascular diseases and cancer. Eventually, it must to be emphasized that all the
Acknowledgments
CONICYT130037, FONDECYT1120577 (MH), FONDECYT3150328 (MKDLF). The figures were produced using Servier Medical Art from www.servier.com.
Marjorie De la Fuente received her Ph.D. degree from the University of Chile, Santiago, Chile, and now is a Postdoctoral Fellow from the National Commission of Science and Technology of Chile. She has recently completed research at the Barts and The London SMD Queen Mary’s School of Medicine and Dentistry, London, UK, under the supervision of Professor Thomas T. MacDonald. She is interested in mucosal immunology, with a focus on intestinal inflammation and the role of macrophages in chronic
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Marjorie De la Fuente received her Ph.D. degree from the University of Chile, Santiago, Chile, and now is a Postdoctoral Fellow from the National Commission of Science and Technology of Chile. She has recently completed research at the Barts and The London SMD Queen Mary’s School of Medicine and Dentistry, London, UK, under the supervision of Professor Thomas T. MacDonald. She is interested in mucosal immunology, with a focus on intestinal inflammation and the role of macrophages in chronic inflammation that can drive carcinogenesis.
Thomas T. MacDonald is a Professor of Immunology and Dean of Research at Barts and The London Queen Mary’s School of Medicine and Dentistry, London, UK. He is interested in understanding how inappropriate immune reactions cause disease in the human gut and how regulatory signaling pathways prevent gut inflammation.
Marcela A. Hermoso is a Professor of Immunology at the Disciplinary Program of Immunology of the Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile. Her research focuses on the pathogenesis of intestinal inflammation and how altered immune responses can promote the ensuing diseases.