IL-33 and ST2 in Atopic Dermatitis: Expression Profiles and Modulation by Triggering Factors

Abstract

In the acute phase of atopic dermatitis (AD), T-helper type 2 (Th2) cytokines characterize the inflammatory response in the skin. IL-33 is a new tissue-derived cytokine, which is mainly expressed by cells of barrier tissues, and is known to activate Th2 lymphocytes, mast cells, and eosinophils. IL-33 signals through a receptor complex consisting of IL-33-specific receptor ST2 and a co-receptor IL-1RAcP. As IL-33 is known to promote Th2-type immunity, we examined expression profiles of IL-33 and its receptor components in human AD skin, in the murine model of AD, and in various cell models. We found increased expression of IL-33 and ST2 in AD skin after allergen or staphylococcal enterotoxin B (SEB) exposure, as well as in the skin of 22-week-old filaggrin-deficient mice. In addition, skin fibroblasts, HaCaT keratinocytes, primary macrophages, and HUVEC endothelial cells efficiently produced IL-33 in response to the combined stimulation of tumor necrosis factor-α and IFN-γ, which was further enhanced by a mimetic of double-stranded RNA. Finally, the increased expression of IL-33 and ST2 caused by irritant, allergen, or SEB challenge was suppressed by topical tacrolimus treatment. These results suggest an important role for IL-33-ST2 interaction in AD and highlight the fact that bacterial and viral infections may increase the production of IL-33.

IL-33 Promotes Food Anaphylaxis in Epicutaneously-Sensitized Mice By Targeting Mast Cells

“…These results indicate that IL-33 released upon mechanical skin injury can potentially target ST2-expressing cells, including MCs, at distant sites. AD often involves more than 10% of the total body surface area, and the median IL-33 level in AD patients serum is more than 10 folds that of healthy controls 16 , 46 . These observations suggest that the mouse model we have used to examine the role of IL-33 in food anaphylaxis following EC sensitization is relevant to patients with AD.…”

“…Forced IL-33 local overexpression by keratinocytes induces ADlike symptoms 15 . IL-33 levels are increased in the skin lesions and serum of patients with AD 16 , 17 and in mouse skin following EC sensitization with OVA 16 . A polymorphism in the gene coding for ST2, a chain of the IL-33 receptor (IL-33R), has been associated in humans with AD 18 .…”

New insights in the pathogenesis of atopic dermatitis

“…In addition, IL-33 has been shown to downregulate serum-induced expression of human β defensin-2 in keratinocytes (24). Immunohistochemical staining showed an increased number of IL-33 + cells among suprabasal keratinocytes and an increased staining of ST2, an IL-33 receptor, among dermal infiltrates in AD lesions (25). IL-25 increases the expression of IL-5 and IL-13 in TSLP-DC-activated T cells (26).…”

Group 2 Innate Lymphoid Cells in Health and Disease

“…Lesional human AD skin has elevated expression of epithelial cell-derived cytokines that promote ILC2 responses including IL-25, IL-33, and TSLP (Soumelis et al 2002;Hvid et al 2011;Deleuran et al 2012;Savinko et al 2012), and ILC2s have been identified in both murine and human skin and are enriched in the lesional skin of human AD patients (Kim et al 2013a;Roediger et al 2013). Although IL-33 has emerged as the dominant cytokine in the activation of ILC2s from murine lung , human blood, and nasal polyps (Mjosberg et al 2012), the original studies identifying skin ILC2s found that murine skin ILC2s are IL-33-and IL-25-independent but dependent on TSLP for their activation during murine AD-like disease (Kim et al 2013a).…”