Molecular Mechanisms Underlying IL-33-Mediated Inflammation in Inflammatory Bowel Disease Part 1

Abstract:

Interleukin-33 (IL-33) is a cytokine defined by its pleiotropic function, acting either as a typical extracellular cytokine or as a nuclear transcription factor. IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), interact with both innate and adaptive immunity and are considered critical regulators of inflammatory disorders. The IL-33/ST2 axis is involved in the maintenance of intestinal homeostasis; based on their role as pro- or anti-inflammatory mediators of first-line innate immunity, their expression is of great importance regarding mucosal defenses. Mucosal immunity commonly presents an imbalance in inflammatory bowel disease (IBD). 

This review summarizes the main cellular and molecular aspects of IL-33 and ST2, mainly focusing on the current evidence of the pro- and anti-inflammatory effects of the IL-33/ST2 axis in the course of ulcerative colitis and Crohn’s disease, as well as the molecular mechanisms underlying the association of IL-33/ST2 signaling in IBD pathogenesis. Although IL-33 modulates and impacts the development, course, and recurrence of the inflammatory response, the exact role of this molecule is elusive, and it seems to be associated with the subtype of the disease or the disease stage. The unraveling of IL-33/ST2-mediated mechanisms involved in IBD pathology shows great potential for clinical application as therapeutic targets in IBD treatment.

Nuclear transcription factors are an important class of proteins that play an important role in gene expression and regulation. In the immune system, nuclear transcription factors participate in the regulation of many immune responses, thus affecting the body's immunity.

Specifically, nuclear transcription factors can control the proliferation, differentiation, and function of immune cells, regulate the interaction between immune cells, and promote or inhibit the occurrence and development of immune responses. For example, transcription factors such as NF-κB, AP-1, and STAT are involved in the activation and differentiation of many immune cells, affecting the survival and function of immune cells; while transcription factors such as FOXP3, T-bet, and GATA3 regulate immune responses The differentiation and function of different types of immune cells in the human body affect the type and extent of the immune response.

Therefore, nuclear transcription factors are closely related to immunity. For the body, maintaining the balance of nuclear transcription factors and properly regulating their activity can promote the enhancement of immunity and prevent the occurrence of many immune-related diseases. Therefore, we need to pay attention to improving our immunity. Cistanche has a significant effect on improving immunity. Meat ash contains various biologically active ingredients, such as polysaccharides, two mushrooms, Huang Li, etc. These ingredients can stimulate the immune system of various types of cells, increasing their immune activity.

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Keywords:

intereukin-33; ST2 receptor; Crohn’s disease; ulcerative colitis; inflammatory bowel disease; pathogenesis.

1. Introduction

Inflammatory bowel disease (IBD) is a term mainly used to describe two chronic autoimmune gastrointestinal diseases: ulcerative colitis (UC) and Crohn’s disease (CD). These disorders are characterized by uncontrolled adaptive and innate immune responses resulting in sustained mucosal inflammation. The mechanisms underlying IBD pathogenesis are a topic of great interest [1,2]. 

The interplay between environmental factors and genetic predisposition, defects in the gut barrier integrity, changes in the gut microbiota community, and impaired regulation of immune responses are the dominant contributing factors related to the pathogenesis and development of IBD [3–10]. The complex interaction between the adaptive and innate immune responses is mediated by various cytokines; disturbance in this crosstalk may result in the instigation and propagation of mucosal inflammation. Interleukin (IL)-1, an integral mediator of innate immune responses, constitutes a group of 11 proinflammatory and anti-inflammatory cytokines (seven ligands with agonist function (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ) and four antagonist ligands (IL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38) [11]. The precursor protein length and the N-terminal segments for each precursor, lead to the segregation of the IL-1 group into three subfamilies: IL-1, IL-18, and IL-36. The IL-1 subfamily is composed of the cytokines IL-1α, IL-1β, and IL-33, and it carries the largest segments [11]. 

This family critically contributes to the regulation of inflammatory responses, repair of impaired tissue, and maintenance of intestinal homeostasis by the stimulation of signaling pathways involved in innate immune responses [12]. Specifically, IL-33 acts as a major mediator of tissue damage and an interface between innate and adaptive immunity. Dysregulation of IL-33 and its receptor signaling has been strongly implicated in a variety of inflammatory diseases, including IBD [13–16], highlighting this cytokine as a critical molecule of mucosal immunity.

This review provides an overview of the cellular and molecular characteristics of IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), describes the current evidence on the pro- and anti-inflammatory effects of IL-33/ST2 axis in the course of UC and CD, and discusses the molecular mechanisms underlying the complex association between the IL-33/ST2 signaling axis and IBD pathogenesis.

2. IL-33 Biological Function

IL-33, also known as IL-F11, was originally discovered as an activator of T helper type 2 (Th2) cells [17,18]. IL-33, a 30 kDa protein, composed of 270 amino acids, plays an important role in the maintenance of tissue homeostasis and repair, in type 2 immune responses, in inflammation induced by allergic and nonallergic triggers, and in viral infections and malignancies [19,20]. This cytokine is commonly released in response to apoptosis, cellular damage, mechanical stress, or immune response stimulation as a full-length biologically active molecule, and it is considered a member of the “alarmins” family [20] (Figure 1).

Growing evidence has highlighted IL-33 as a pleiotropic cytokine, which not only activates the Th2 cells but also induces Th1 cells, group 2 innate lymphoid cells (ILC2s), and T regulatory cells (Tregs) [17,18]. Beyond adaptive immunity, IL-33 is expressed by a wide variety of cell types including tissue-derived cells, vascular endothelium, epithelial barrier, stromal fibroblasts, and antigen-presenting cells (APCs), upon encountering microbial infection, exposure to allergens, or tissue damage [17,18]. IL-33 release leads to the stimulation of myeloid differentiation primary response 88 (MyD88)-dependent signaling pathways in cells expressing the interleukin 1 receptor-like 1, also known as IL1RL1 and ST2 [21] (Figure 2).

Figure 2. Activation of IL-33/ST2 signaling. Full-length IL-33 is composed of an N-terminal nuclear domain and a C-terminal IL-1-like cytokine domain, divided by a central domain. IL-33 signals through a great variety of immune cells promoting their function. The binding of IL-33 to the sST2 decoy receptor prevents the ST2/IL-33 signaling, whereas the binding of IL-33 to ST2 results in the activation of the transcription factor NF-κB and the MAP kinases, leading to related-gene transcription. This figure was created with BioRender (https://biorender.com (accessed on 29 November 2022)). IL-33, interleukin-33; ST2, suppression of tumorigenicity 2; sST2, soluble ST2; IL-1RAcP, IL-1 receptor accessory protein; MyD88, myeloid differentiation primary response 88; TRAF6, tumor necrosis factor receptor-associated factor 6; IRAK 1, interleukin receptor-associated kinase; NF-κB, nuclear factor κB; MAPK, mitogen-activated protein kinases; AP-1, activator protein 1; Th1 cells, T helper 1 cell; Treg cells, T regulatory cells; DC cells, dendritic cells; CD8 cells, cytotoxic T cells; NK cells, natural killer cells; iNKT cells, invariant natural killer T cells; ILC2 cells, group 2 innate lymphoid cells.

2.1. IL-33/ST2 Signaling

ST2 is a full-length, membrane-spanning receptor that exists in two different forms as splice variants, the soluble form (sST2) and the membrane-bound form. The sST2 form acts as a decoy receptor and is responsible for the sequestering of free IL-33, whereas ST2 induces the MyD88/nuclear factor κB (NF-κB) signaling pathway to promote the function of immune cells [22]. ST2 is constitutively expressed in various immune cells, including Th1 cells, Th2 cells, cytotoxic T cells (CD8), Tregs, ILC2 cells, mast cells, M2 polarized macrophages, neutrophils, basophils, eosinophils, natural killer (NK) cells, and invariant natural killer T (iNKT) cells [17,19,23,24]. ST2 is also expressed in other cell types; however, its expression is inducible and depends on the cellular microenvironment. Although IL-33 is highly expressed in the mucosal tissue and myofibroblasts, ST2 is mainly expressed in immune cells, allowing the IL-33/ST2 axis to act as a bridge between immune system orchestration and tissue injury, which is probably considered an essential component in intestinal immune responses [12]. IL-12 induces the ST2 expression on Th1 cells and on cytotoxic T cells, whereas IL-33 expression is critical for the activation of these cell populations [25,26]. IL-33 acts at both intracellular and extracellular levels. Intracellularly, IL-33 modulates the expression of various genes, acting as a nuclear factor [20]. 

Extracellularly, IL-33 operates as a cytokine, activating immune cells [20]. The human IL-33 contains an N-terminal nuclear localization signal (NLS) which controls the cytokine transfer to the nucleus, a central domain characterized as a “protease sensor” domain, and a C-terminal, IL-1-like region with cytokine activity [19,27,28]. Several proteases are accountable for the cleavage of the IL-33 within its central domain and produce the mature IL-33 form [29]. Conversely, cleavage of IL-33 by caspases into the IL-1-like domain during apoptosis leads to the inactivation of the molecule [29,30]. This process reduces IL-33 biological activity, leading to the hypothesis that the presence of extracellular proteases can inactivate the full-length IL-33, averting potential detrimental effects induced by high circulating IL-33 levels [31]. 

However, in the microenvironment of inflammation, the N-terminal proteolytic cleavage by the proteases, neutrophil elastase, and cathepsin G, can elevate its potency [32], underlying IL-33 in modulating the response to cellular damage.

IL-33 binds to its transmembrane receptor ST2, followed by a conformational alteration which results in the interaction of ST2 with the IL-1 receptor accessory protein (IL1RAcP), a crucial molecule for IL-33 signaling [17,33]. The IL-33/ST2/IL1-RAcP complex is accountable for the Toll–interleukin receptor (TIR) dimerization [17]. This complex promotes intracellular signaling via the differentiation of MyD88, interleukin receptor-associated kinase (IRAK) 1 and 4, and tumor necrosis factor receptor-associated factor 6 (TRAF6) [17,27]. Through the aforementioned mechanisms, the mitogen-activated protein (MAP) kinases and NF-κB become activated, promoting the inflammatory cascade. In parallel, this complex induces the expression of the extracellular signal-regulated kinase (ERK) and Jun kinase, which in turn promotes the downregulation of forkhead box p3 (Foxp3) and GATA3 transcription factors [20].

The significance of nuclear IL-33 sequestration and the great potency of IL-33/ST2 signaling in developing acute inflammation was presented by Carriere et al. The results of this study demonstrated that an alteration in the N-terminal part of IL-33 impeded the interaction of the cytokine with chromatin, resulting in the development of an inflammatory response, with splenomegaly, elevated lymph node influx, and colitis development [34]. Genetic ablation of ST2 led to the cessation of the inflammatory response [34]. These findings indicate the role of IL-33/ST2 signaling as a bridge between tissue damage and orchestration of the immune system, which may critically contribute to the maintenance of intestinal immunity.

2.2. IL-33/ST2 Signaling and Mucosal Immunity

Beyond the role of the IL-33/ST2 signaling pathway as a front-line herald of intestinal tissue damage, IL-33/ST2 also connects the innate and adaptive immunity with the host mucosal immunity, by inducing the type 2 response in T cells, ILCs, and macrophages [35,36]. An interesting aspect of IL-33 is its role as an alarmin, acting at the barrier tissue, driving inflammation and fibrosis during acute mucosal damage [37]. 

The biologically active molecule of IL-33 is located in the nucleus bound to chromatin [34]. Cell lysis leads to the recruitment of neutrophils, eosinophils, and NK cells by IL-33, as well as the proliferation of type 2 cells, thus commencing the fibrotic process and wound healing [38,39]. During this procedure, IL-33 also acts as a transcriptional factor and, through its binding to the p65 subunit of NF-κB, promotes the activation of endothelial cells [40].

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