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Selected Publication:

Type of publication: Journal Article
Type of document: Full Paper

Year: 2021

Authors: Poelzl, A; Lassnig, C; Tangermann, S; Hromadová, D; Reichart, U; Gawish, R; Mueller, K; Moriggl, R; Linkermann, A; Glösmann, M; Kenner, L; Mueller, M; Strobl, B

Title: TYK2 licenses non-canonical inflammasome activation during endotoxemia.

Source: Cell Death Differ. 2021 28 (2) 748-763.

Authors Vetmeduni Vienna:

Gawish Riem
Glösmann Martin
Hromadova Dominika
Kenner Lukas
Lassnig Caroline
Moriggl Richard
Müller Kristina
Müller Mathias
Pölzl Andrea
Reichart Ursula
Strobl Birgit
Tangermann Simone

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics
Institute of Animal Breeding and Genetics, Unit of Molecular Genetics

Project(s): Tyk2 in the innate immune response during sepsis

Molecular and Cellular Control of Tissue Homeostasis in Health and Disease

The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptor-associated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1β and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1β and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrow-derived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.

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