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A8.6 Interleukin 33 skin overexpression does not induce inflammation
  1. Olga Wagner1,
  2. Verena Kästele1,
  3. Verena Schmitt1,
  4. Anja Derer1,
  5. Dieter Engelkamp1,
  6. Derek Gilchrist2,
  7. Iain B McInnes2,
  8. Georg Schett1,
  9. Silke Frey1,
  10. Axel J Hueber1
  1. 1University Hospital of Erlangen, Department of Rheumatology and Immunology, Erlangen, Germany
  2. 2Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK


Background The cytokine interleukin 33 (IL-33), a member of the IL-1 family, is released in response to various types of endothelial or epithelial cell damage. IL-33 is constitutively expressed in epidermal keratinocytes, upregulated in inflamed skin and acts as an endogenous danger signal that mediates the recruitment of immune cells to sites of cellular damage. Our preliminary data have shown that psoriatic lesions express more nuclear IL-33 compared to perilesional biopsies from the same patients and mature IL-33 induces skin inflammation in a mouse model.

Objectives To determine the role and function of IL-33 in skin inflammation, in particular to understand the mechanism how IL-33 contributes to the pathology and recruitment of inflammatory cells.

Materials and Methods Transgenic mice with skin-specific expression of full length IL-33 were generated via pronuclear injection of K14-IL-33. This construct with IL-33 under keratin 14 promotor was tested for the functionality in vitro following the generation of the transgenic mice. For analysis control littermates with no transgene were used. K14-IL-33 mice were tested in various skin inflammation models including TLR7 agonistic stimulation with imiquimod 5%, ear injection model (rIL-23, 500 ng/ear for 14 days), and skin tape stripping. As readout we used caliper measurement of the ear thickness, skin histology H&E staining and immunohistochemistry as well as mRNA expression by quantitative RT-PCR.

Results Pronuclear injection resulted in 16 pups with 2 transgenic mice expressing the IL-33 transgene. K14-IL-33 mice were born and developed normally with no obvious phenotype. Increased expression in the skin in K14-IL-33 compare to wildtype (WT) mice was detected using RT-PCR and immunohistology; as expected IL-33 was localised in the nuclei of the keratinocytes. No significant expression was measured in other organs. Due to the lack of a skin phenotype we performed different skin inflammation models in the K14-IL-33 mouse. Neither TLR7 stimulation via imiquimod, ear injection of IL-23, a pivotal cytokine for psoriasis, nor skin tape stripping as a model for chronic skin damage induced a clinical/histological change compared to littermates.

Conclusions We demonstrate that local skin overexpression of the alarmin IL-33 does not induce spontaneous or triggered skin inflammation. In comparison to a published K14-IL-33 mouse with atopic inflammatory phenotype our data could not reproduce the described phenotype. These data suggest that different expression thresholds might lead to exacerbation of skin diseases.

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