PMID- 32929218 OWN - NLM STAT- MEDLINE DCOM- 20211215 LR - 20221018 IS - 1476-5403 (Electronic) IS - 1350-9047 (Print) IS - 1350-9047 (Linking) VI - 28 IP - 2 DP - 2021 Feb TI - TYK2 licenses non-canonical inflammasome activation during endotoxemia. PG - 748-763 LID - 10.1038/s41418-020-00621-x [doi] AB - 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-1beta and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1beta 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. FAU - Poelzl, Andrea AU - Poelzl A AUID- ORCID: 0000-0002-4005-7728 AD - Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. AD - Biomodels Austria, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Lassnig, Caroline AU - Lassnig C AD - Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. AD - Biomodels Austria, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Tangermann, Simone AU - Tangermann S AD - Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Hromadova, Dominika AU - Hromadova D AUID- ORCID: 0000-0002-7888-0090 AD - Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Reichart, Ursula AU - Reichart U AD - VetCORE - Facility for Research, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Gawish, Riem AU - Gawish R AD - Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Mueller, Kristina AU - Mueller K AD - Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Moriggl, Richard AU - Moriggl R AD - Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Linkermann, Andreas AU - Linkermann A AD - Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische University of Dresden, 01069, Dresden, Germany. FAU - Glosmann, Martin AU - Glosmann M AD - VetCORE - Facility for Research, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Kenner, Lukas AU - Kenner L AUID- ORCID: 0000-0003-2184-1338 AD - Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Mueller, Mathias AU - Mueller M AD - Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. AD - Biomodels Austria, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. FAU - Strobl, Birgit AU - Strobl B AUID- ORCID: 0000-0001-5716-3212 AD - Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria. birgit.strobl@vetmeduni.ac.at. LA - eng GR - F 6101/FWF_/Austrian Science Fund FWF/Austria GR - F 6106/FWF_/Austrian Science Fund FWF/Austria GR - DOC 32/FWF_/Austrian Science Fund FWF/Austria GR - P 25642/FWF_/Austrian Science Fund FWF/Austria GR - F 6105/FWF_/Austrian Science Fund FWF/Austria PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200914 PL - England TA - Cell Death Differ JT - Cell death and differentiation JID - 9437445 RN - 0 (Inflammasomes) RN - 0 (Interleukin-18) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - EC 2.7.10.2 (TYK2 Kinase) RN - EC 2.7.10.2 (TYK2 protein, human) RN - EC 3.4.22.- (Casp4 protein, mouse) RN - EC 3.4.22.- (Caspases, Initiator) SB - IM MH - Animals MH - Caspases, Initiator/*metabolism MH - Endotoxemia/drug therapy MH - Female MH - Humans MH - Inflammasomes/*drug effects/immunology/metabolism MH - Interleukin-18/metabolism MH - Interleukin-1beta/metabolism MH - Lipopolysaccharides/toxicity MH - Macrophages/*drug effects/immunology/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Myeloid Cells/drug effects/immunology/metabolism MH - Pyroptosis/*drug effects MH - TYK2 Kinase/*pharmacology MH - U937 Cells PMC - PMC7862449 COIS- The authors declare that they have no conflict of interest. EDAT- 2020/09/16 06:00 MHDA- 2021/12/16 06:00 PMCR- 2020/09/14 CRDT- 2020/09/15 05:45 PHST- 2020/01/07 00:00 [received] PHST- 2020/09/01 00:00 [accepted] PHST- 2020/08/31 00:00 [revised] PHST- 2020/09/16 06:00 [pubmed] PHST- 2021/12/16 06:00 [medline] PHST- 2020/09/15 05:45 [entrez] PHST- 2020/09/14 00:00 [pmc-release] AID - 10.1038/s41418-020-00621-x [pii] AID - 621 [pii] AID - 10.1038/s41418-020-00621-x [doi] PST - ppublish SO - Cell Death Differ. 2021 Feb;28(2):748-763. doi: 10.1038/s41418-020-00621-x. Epub 2020 Sep 14.