IL-33 and the intestine: The good, the bad, and the inflammatory

Abstract

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family that has been widely studied since its discovery in 2005 for its dichotomous functions in homeostasis and inflammation. IL-33, along with its receptor suppression of tumorigenicity 2 (ST2), has been shown to modulate both the innate and adaptive immune system. Originally, the IL-33/ST2 signaling axis was studied in the context of inducing type 2 immune responses with the expression of ST2 by T helper 2 (T_H2) cells. However, the role of IL-33 is not limited to T_H2 responses. Rather, IL-33 is a potent activator of T_H1 cells, group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, and CD8⁺ T cells. The intestine is uniquely important in this discussion, as the intestinal epithelium is distinctively positioned to interact with both pathogens and the immune cells housed in the mucosa. In the intestine, IL-33 is expressed by the pericryptal fibroblasts and its expression is increased particularly in disease states. Moreover, IL-33/ST2 signaling aberrancy is implicated in the pathogenesis of inflammatory bowel disease (IBD). Accordingly, for this review, we will focus on the role of IL-33 in the regulation of intestinal immunity, involvement in intestinal disease, and implication in potential therapeutics.

Keywords: Inflammatory bowel disease; Interleukin-33; Intestinal immunity; Microbiome; T cells.

Figure 1. The role of IL-33 in intestinal immunity

IL-33 is expressed by several epithelial cell types including the epithelial cells of the intestinal mucosa. In response to cell injury, IL-33 is released from the injured cell to recruit the immune system, thereby behaving as an alarmin. The IL-33 receptor, ST2, is expressed on several immune cells of the intestine, including T_H2 cells, ILC2s, Tregs, and T_H1 cells. Upon activation of these cells, there are increased efforts to repair the epithelium. However, the stromal cells and epithelial cells are capable of releasing sST2, which acts as a receptor decoy, thereby limiting IL-33 induced inflammation. The intestine also readily cooperates with commensal bacteria and pathogenic bacteria. IL-33 has been shown to interact with the gut microbiome and IgA to promote intestinal immunity. On a cellular level, IL-33 is released from the epithelial cell as active IL-33, which can then be acted upon by inflammatory proteases from neutrophils and mast cells to produce mature IL-33. Mature IL-33 is significantly more potent in this state and can accordingly activate the immune system more efficiently. However, there are several mechanisms in place to limit its response to cell injury and death. One such example is cleavage by caspases 3 and 7 by apoptotic cells to deactivate IL-33 before its release. This inhibits IL-33 activity and the subsequent inflammatory response.

Figure 2. Isoforms of IL-33 receptor ST2

There are four isoforms of ST2 encoded by the gene ST2 located on human chromosome 2q12. The two most prominent isoforms include transmembrane ST (ST2L also known as IL1RL1-b) and soluble ST (sST2, IL1RL1-a). They are the consequence of a dual promotor system that results in differential mRNA expression. ST2L, like other type 1 IL-1 receptors, is comprised of an extracellular domain, transmembrane domain, and cytoplasmic domain, whereas sST2 does not possess the transmembrane and cytoplasmic domains and thus exists as a soluble protein. Moreover, alternative splicing results in the formation of ST2V and ST2LV. ST2V shares the same extracellular and transmembrane domains as ST2L, but is notable for its unique hydrophobic tail and it is particularly enriched in the gastrointestinal tract. Lastly, ST2LV remarkably lacks the transmembrane domain of ST2L but maintains the intracellular domain, suggesting it exists as a soluble protein.