IL-33's role in the gut immune system: A comprehensive review of its crosstalk and regulation

The intestinal tract is the largest immune organ in the human body, comprising a complex network of immune cells and epithelial cells that perform a variety of functions such as nutrient absorption, digestion, and waste excretion. Maintenance of homeostasis and effective responses to injury in the colonic epithelium are crucial for maintaining homeostasis between these two cell types. The onset and perpetuation of gut inflammation, characterizing inflammatory bowel diseases (IBD), are triggered by constitutive dysregulation of cytokine production. IL-33 is a newly characterized cytokine that has emerged as a critical modulator of inflammatory disorders. IL-33 is constitutively expressed in the nuclei of different cell types such as endothelial, epithelial, and fibroblast-like cells. Upon tissue damage or pathogen encounter, IL-33 is released as an alarmin and signals through a heterodimer receptor that consists of serum Stimulation-2 (ST2) and IL-1 receptor accessory protein (IL-1RAcP). IL-33 has the ability to induce Th2 cytokine production and enhance both Th1 and Th2, as well as Th17 immune responses. Exogenous administration of IL-33 in mice caused pathological changes in most mucosal tissues such as the lung and the gastrointestinal (GI) tract associated with increased production of type 2 cytokines and chemokines. In vivo and in vitro, primary studies have exhibited that IL-33 can activate Th2 cells, mast cells, or basophils to produce type 2 cytokines such as IL-4, IL-5, and IL-13. Moreover, several novel cell populations, collectively referred to as “type 2 innate lymphoid cells” were identified as being IL-33 responsive and are thought to be important for initiating type 2 immunity. Nevertheless, the underlying mechanisms by which IL-33 promotes type 2 immunity in the GI tract remain to be fully understood. Recently, it has been discovered that IL-33 plays important roles in regulatory immune responses. Highly suppressive ST2 + FoxP3+ Tregs subsets regulated by IL-33 were identified in several tissues, including lymphoid organs, gut, lung, and adipose tissues. This review aims to comprehensively summarize the current knowledge on IL-33's role in the gut immune system, its crosstalk, and regulation. The article will provide insights into the potential applications of IL-33-based therapies in the treatment of gut inflammatory disorders.