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Role of the IL-1beta-processing inflammasome in the pathogenesis os severe skin disease

English title Role of the IL-1beta-processing inflammasome in the pathogenesis os severe skin disease
Applicant French Lars Einar
Number 120400
Funding scheme Project funding
Research institution Dermatologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Dermatology
Start/End 01.05.2008 - 30.04.2011
Approved amount 450'000.00
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Keywords (6)

Interleukin-1; inflammation; skin; squamous cell carcinoma; inflammasome; graft-versus-host disease

Lay Summary (English)

Lead
Lay summary
An innate immune response can be triggered by the assembly of the inflammasome, a newly identified cytosolic complex of proteins that activates caspase-1 and/or -5 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. Activation of inflammasome assembly is mediated by certain “danger signals” and bacterial components. NALPs are the central proteins in the inflammasome complex and belong to the family of NOD-like receptors that also includes the NOD proteins. IL-1beta is a key pro-inflammatory cytokine that is known to mediate acute immune responses and provide a link between the innate and adaptive immune responses. We have recently shown that inflammasome assembly in keratinocytes can be induced by contact allergens and contribute to inflammation in a mouse model of contact dermatitis. Moreover, we demonstrated that the inflammasome acts as a master switch between tolerance and sensitization to irritant chemicals in the skin. Several observations support a role for the innate immunity, including production of IL-1beta or IL-18 pro-inflammatory cytokines in the pathogenesis of selected severe skin diseases among which are graft-versus-host disease (GVHD) and squamous cell carcinoma (SCC). In the present project, we propose to analyze the role of the IL-1beta-processing inflammasome in the early pathogenesis of these 2 severe skin diseases and the potential of inflammasome inhibitors for their treatment and/or prophylaxis. To do so we will make use of novel tools available in our laboratory, including inflammasome-deficient mice and appropriate murine models of GVHD and SCC. Briefly, acute GVHD will be induced by infusing allogeneic T cells in irradiated hosts, SCC will be induced by DMBA and repeated TPA applications on the skin. Both TPA and DMBA are well described carcinogens. In both models, the occurrence and severity of the diseases as well as quantitative and qualitative aspects of the local inflammatory responses will be analyzed. In addition to the analysis of the role of inflammasome using inflammasome-deficient mice in the pathogenesis of these skin reactions, inflammasome inhibitors such as geldanamycin and its analogue 17-DMAG will be tested in both models. In addition to murine model, a correlation with the human setting will be studied by immunohistochemichal analysis of IL-1beta and capase-1 activity in selected skin biopsies. This work should allow us to better understand the role of the inflammasome in immune responses relevant to human disease, as well as further our understanding of the pathogenesis of GVHD and SCC, and possibly identify new therapeutic targets.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
135465 Investigation of the role of the inflammasome and IL-1beta in the pathogenesis of inflammatory acne and acneiform skin disease caused by EGF-R inhibitors 01.05.2011 Project funding

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