Skip to main content

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

Objective

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.

Call for proposal

ERC-2013-StG
See other projects for this call

Host institution

UNIVERSITAETSKLINIKUM FREIBURG
Address
Hugstetter Strasse 49
79106 Freiburg
Germany

See on map

Activity type
Higher or Secondary Education Establishments
Administrative Contact
Gerhard Henninger (Mr.)
Principal investigator
Olaf Groß (Dr.)
EU contribution
€ 541 715,75

Beneficiaries (2)

UNIVERSITAETSKLINIKUM FREIBURG
Germany
EU contribution
€ 541 715,75
Address
Hugstetter Strasse 49
79106 Freiburg

See on map

Activity type
Higher or Secondary Education Establishments
Administrative Contact
Gerhard Henninger (Mr.)
Principal investigator
Olaf Groß (Dr.)
KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Germany
EU contribution
€ 953 817,25
Address
Ismaninger Strasse 22
81675 Muenchen

See on map

Activity type
Higher or Secondary Education Establishments
Administrative Contact
Beate Schaulin (Ms.)