Abstract
The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction.
Highlights
The cytokine interleukin 33 (IL-33) is a member of the IL-1 family contributing to pathogenesis in allergic lung diseases [1, 2], atopic dermatitis [3], sepsis [4], inflammatory tendinopathy [5] and to rheumatoid arthritis [6] and psoriasis [7]
If mature IL-33 exclusively linked to keratinocytes induce spontaneous inflammation we used an inducible K14-IL-33-CRETM/ GFPmmIL33 mouse
This mouse contains a transgene DNA with loxP-flanked GFP and stop codon, which prevents transcription of the mature form of mouse IL-33 cDNA and was crossed with a tamoxifen inducible K14-CreERTM mouse (Figures 1A,B)
Summary
The cytokine interleukin 33 (IL-33) is a member of the IL-1 family contributing to pathogenesis in allergic lung diseases [1, 2], atopic dermatitis [3], sepsis [4], inflammatory tendinopathy [5] and to rheumatoid arthritis [6] and psoriasis [7]. IL-33 is constitutively expressed in epithelial cells from tissues with a barrier function, as well as in endothelial cells and fibroblasts [8]. IL-33 in Irradiation-Induced Skin Reaction types of endothelial or epithelial cell damage, IL-33 is released and binds to the heterodimeric receptor complex ST2L/IL1RacP expressed on Th2 and diverse types of innate immune cells [9,10,11]. As alarmin, released during cell damage, IL-33 activates the immune system [12, 15]. IL-33 will be cleaved by activated caspase 3 and 7 in the IL-1-like cytokine domain. This short form of IL-33 has an attenuated biological activity and no capacity to activate the immune system [16]. Active externalization of IL-33 has been described by stimulation with proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) [18]
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