Die Rolle des Inflammasomkomplexes bei der Induktion T-Zell-spezifischer Immunantworten
Final Report Abstract
Aim of the studies was to characterize innate immunity and in particular IL-1 activation and signaling in skin inflammation. We first determined the presence of the essential components of the Nlrp3- inflammasome in both human and murine keratinocytes. While human primary keratinocytes responded to stimulation with skin irritants such as TNCB, UVB irradiation or the bacterial toxin Nigericin with robust secretion of IL-1ß, murine skin was unable to secrete IL-1ß. To elucidate the mechanism of lL-1ß-secretion we ruled out NKGDL-activation as one possible mechanism to mediate danger signals. In a model of inflammasome activation, we demonstrated the capacity of nanoparticles to activate the Nlrp3-inflammasome both in myeloid and non-myeloid cells. Nano-TiO2 and nano-SiO2, but not nano-ZnO, activate the NLRP3 inflammasome, leading to IL-Iß release and in addition, induce the regulated release of IL-1α. As the capacity of cells to release IL-1α upon stimulation with Nlrp3- agonists, we further investigated the dependence of IL-1α secretion from the inflammasome and we could demonstrate a partial dependence of the secretion of the cytokine on the presence of the inflammasome components ASC and Nlrp3. To confirm our findings in vivo we exposed mice with the intraperitoneal injection or the inhalation of nano-TiO2. Both in vivo modes of exposition prorovoked an inflammatory response which is strongly suppressed in IL-1R- and IL-1α-deficient mice, drawing the first in vivo and ex vivo links between the inflammasome and the IL-1α-pathway, which is currently under further investigation.
Publications
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Inflammatory caspases in innate immunity and inflammation. J Innate Immun. 2010;2:228-37
Yazdi AS, Guarda G, D'Ombrain MC, Drexler SK
