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Inflammasome-induced IL-1 Secretion: Route, Mechanism, and Cell Fate

Objetivo

Inflammasomes are intracellular danger-sensing protein complexes that are important for host protection. They initiate inflammation by controlling the activity of the proinflammatory cytokine interleukin-1β (IL-1β). Unlike most other cytokines, IL-1β is produced and retained in the cytoplasm in an inactive pro-form. Inflammasome-dependent maturation of proIL-1β is mediated by the common component of all inflammasomes, the protease caspase-1. Caspase-1 also controls the secretion of IL-1β, but the mechanism and route of secretion are unknown. We have recently demonstrated that the ability of caspase-1 to control IL-1β secretion is not dependent on its protease activity, but rather on a scaffold or adapter function of caspase-1. Furthermore, we and others could show that caspase-1 can control the secretion of non-substrates like IL-1α. These insights provide us with new and potentially revealing means to investigate the downstream effector functions of caspase-1, including the route and mechanism of IL-1 secretion. We will develop new tools to study the process of IL-1 secretion by microscopy and the novel mode-of-action of caspase-1 through the generation of transgenic models.
Despite the important role of IL-1 in host defence against infection, dysregulated inflammasome activation and IL-1 production has a causal role in a number of acquired and hereditary auto-inflammatory conditions. These include particle-induced sterile inflammation (as is seen in gout and asbestosis), hereditary periodic fever syndromes, and metabolic diseases like diabetes and atherosclerosis. Currently, recombinant proteins that block the IL-1 receptor or deplete secreted IL-1 are used to treat IL-1-dependent diseases. These are costly treatments, and are also therapeutically cumbersome since they are not orally available. We hope that a better understanding of caspase-1-mediated secretion of IL-1 will unveil mechanisms that may serve as targets for future therapies for these diseases.

Convocatoria de propuestas

ERC-2013-StG
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Régimen de financiación

ERC-SG - ERC Starting Grant

Institución de acogida

UNIVERSITAETSKLINIKUM FREIBURG
Aportación de la UE
€ 541 715,75
Dirección
HUGSTETTER STRASSE 49
79106 Freiburg
Alemania

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Región
Baden-Württemberg Freiburg Freiburg im Breisgau, Stadtkreis
Tipo de actividad
Higher or Secondary Education Establishments
Contacto administrativo
Gerhard Henninger (Mr.)
Investigador principal
Olaf Groß (Dr.)
Enlaces
Coste total
Sin datos

Beneficiarios (2)