Epidermal Expression and Regulation of Interleukin-33 during Homeostasis and Inflammation: Strong Species Differences

Abstract

IL-33 is a novel IL-1 family member with a putative role in inflammatory skin disorders and a complex biology. Therefore, recent conflicting data regarding its function in experimental models justify a close assessment of its tissue expression and regulation. Indeed, we report here that there are strong species differences in the expression and regulation of epidermal IL-33. In murine epidermis, IL-33 behaved similar to an alarmin, being constitutively expressed in keratinocyte nuclei and rapidly lost during acute inflammation. By contrast, human and porcine IL-33 were weakly expressed or absent in keratinocytes of noninflamed skin but induced during acute inflammation. To this end, we observed that expression of IL-33 in human keratinocytes but not murine keratinocytes was strongly induced by IFN-γ, and this upregulation completely depended on the presence of EGFR ligands. Accordingly, IFN-γ increased the expression of IL-33 in the basal layers of the epidermis in human ex vivo skin cultures only, despite good evidence of IFN-γ activity in cultures from both species. Together these findings demonstrate that a full understanding of IL-33 function in clinical settings must take species-specific differences into account.

Interleukin-33 and RANK-L Interplay in the Alveolar Bone Loss Associated to Periodontitis

“…IL-33 expression in CP in human has recently been described by Malcolm et al in gingival epithelial cells and our results confirmed this observation [20]. This is of particular interest because differences of IL-33 expression in skin have been reported between species [35]. Notably in human and porcine keratinocytes, IL-33 expression is low but rapidly induced after skin wounding whereas it is the opposite in mice.…”

“…We also recorded such increase 24 hours after Pg infection of human epithelial cells. However, as we also recorded an increased IL-33 expression in vivo independently of Pg infection, it is tempting to speculate that the ligature apposition is an inflammatory stimulus sufficient to induce the increase of IL-33 expression in gingival epithelial cells, directly or throughout other pro-inflammatory cytokines such as TNF-α or IFN-γ [35, 37]. Consistently, we have also observed an IL-33 expression in Sham animals subjected to a slight incision suggesting that this mechanical stimulus may trigger the production of IL-33 in gingival epithelial cell and that Pg may be not the major factor needed for IL-33 expression.…”

Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation

“…IL-33 expression in endothelial cells in vitro has been linked to cellular quiescence and confluence, and may require Notch signals (Küchler et al, 2008; Sundlisaeter et al, 2012). Human and mouse share constitutive IL-33 expression at epithelial surfaces, including in skin, stomach, intestine, salivary gland, vagina and lung, where expression is particularly high in alveolar type 2 cells (Mohapatra et al, 2015; Moussion et al, 2008; Pastorelli et al, 2010; Schmitz et al, 2005); species-specific differences may exist (Sundnes et al, 2015). This epithelial expression pattern partially overlaps with other cytokines that target ILC2s, including TSLP and IL-25, suggesting potentially shared functions (Bulek et al, 2010; Mohapatra et al, 2015).…”

Wounds that heal and wounds that don’t − The role of the IL-33/ST2 pathway in tissue repair and tumorigenesis

“…mast cells, macrophages and DCs. IL-33 can be induced by a variety of immune stimuli, for example proinflammatory TLR ligands, cytokines and immune complexes [7] [8]. Different IL-33 splice variants have been observed in human tissues.…”

“…Although it seems from these reports that IL-33 signalling at the site of cutaneous damage may facilitate the transition of macrophages from a pro-inflammatory to a prorepair phenotype thereby promoting dermal wound healing, the underlying mechanism for IL-33 in skin wound healing remains unclear. Given the interesting observation that IL-33 expression both varies at a basal level and is also differentially regulated between mouse and human keratinocytes [8], it is clear that more detailed studies need to be performed on human tissues and human cell lines to fully elucidate the role of IL-33 in cutaneous wound healing in humans.…”