Role of IL-33 in inflammation and disease

Abstract

Interleukin (IL)-33 is a new member of the IL-1 superfamily of cytokines that is expressed by mainly stromal cells, such as epithelial and endothelial cells, and its expression is upregulated following pro-inflammatory stimulation. IL-33 can function both as a traditional cytokine and as a nuclear factor regulating gene transcription. It is thought to function as an 'alarmin' released following cell necrosis to alerting the immune system to tissue damage or stress. It mediates its biological effects via interaction with the receptors ST2 (IL-1RL1) and IL-1 receptor accessory protein (IL-1RAcP), both of which are widely expressed, particularly by innate immune cells and T helper 2 (Th2) cells. IL-33 strongly induces Th2 cytokine production from these cells and can promote the pathogenesis of Th2-related disease such as asthma, atopic dermatitis and anaphylaxis. However, IL-33 has shown various protective effects in cardiovascular diseases such as atherosclerosis, obesity, type 2 diabetes and cardiac remodeling. Thus, the effects of IL-33 are either pro- or anti-inflammatory depending on the disease and the model. In this review the role of IL-33 in the inflammation of several disease pathologies will be discussed, with particular emphasis on recent advances.

Figure 1

IL-33 release and signaling via ST2L. IL-33 is predominantly expressed by stromal cells such as epithelial and endothelial cells. Damage to these cells can induce necrosis and release of full length IL-33 which can activate the heterodimeric ST2L/IL-1RAcP receptor complex on a variety of immune cells or be neutralized by binding to sST2. During apoptosis IL-33 is cleaved by caspases-3/7 leading to its inactivation. Upon activation of ST2L MyD88 and IRAK-1/4 are recruited and this leads to activation of the transcription factor nuclear factor-κB (NF-κB) and the mitogen-activated protein kinase (MAPK) pathway, which is mediated by the activation of the MAPKs extracellular signal-regulated kinase (ERK), p38 and JUN N-terminal kinase (JNK) and ultimately to the production of Th2 cytokines and chemokines.

Figure 2

Schematic representation of the potential pro-inflammatory role of IL-33 in normal skin and in skin inflammation (atopic dermatitis and psoriasis). Damage to the skin such as by scratching in response to an allergen and inflammation lead to cell necrosis and release of biologically active IL-33. IL-33 can interact with its receptor ST2L on a number of cell types within the skin, including resident skin cells and infiltrating immune cells. IL-33 may drive dendritic cell (DC) mediated polarization of naïve CD4⁺ T cells towards a Th2 phenotype and the production of cytokines such as IL-5, IL-10 and IL-13. IL-33 can also potently activate innate immune cells such as mast cells (MC) leading to release of biologically active mediators such as VEGF, histamine and prostaglandin E2 (PGE2). IL-33 can also lead to production of the chemokine KC, thus recruiting neutrophils (N). An increase in Th17 cells and related cytokines IL-17/22 may be driven by IL-33 stimulation of IL-1 and IL-6 production. Furthermore, IL-33 mediated production of VEGF may drive angiogenesis and skin remodeling.

Figure 3

Schematic representation of the potential ant-inflammatory role of IL-33 in adipose tissue inflammation. Tissue damage caused by factors such as high free fatty acids, ER stress, oxidative stress, and inflammation can lead to necrosis of cells and release of biologically active IL-33. This can interact with its receptor ST2L on a number of cell types within adipose tissue (adipocytes themselves, CD4⁺ Th2 cells and Fat-Associated Lymphoid Cluster (FALC) cells) leading to the production of protective Th2 cytokines (e.g. IL-5, IL-10 and IL-13). IL-33 can polarize macrophages towards an alternatively activated (M2) phenotype and reduce lipid uptake in adipocytes and macrophages via the down-regulation of several metabolic genes.