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The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3.
Gaidt, Moritz M; Ebert, Thomas S; Chauhan, Dhruv; Ramshorn, Katharina; Pinci, Francesca; Zuber, Sarah; O'Duill, Fionan; Schmid-Burgk, Jonathan L; Hoss, Florian; Buhmann, Raymund; Wittmann, Georg; Latz, Eicke; Subklewe, Marion; Hornung, Veit.
Afiliación
  • Gaidt MM; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Ebert TS; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Chauhan D; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Ramshorn K; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Pinci F; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Zuber S; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • O'Duill F; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Schmid-Burgk JL; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Hoss F; Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany.
  • Buhmann R; Department of Transfusion Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Wittmann G; Department of Transfusion Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Latz E; Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
  • Subklewe M; Laboratory for Translational Cancer Immunology, Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • Hornung V; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; Center for Integrated Protein Science (CIPSM), Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address: hornung@genzentrum.lmu.de.
Cell ; 171(5): 1110-1124.e18, 2017 Nov 16.
Article en En | MEDLINE | ID: mdl-29033128
Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Monocitos / Muerte Celular / Inflamasomas / Proteína con Dominio Pirina 3 de la Familia NLR Límite: Humans Idioma: En Revista: Cell Año: 2017 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Monocitos / Muerte Celular / Inflamasomas / Proteína con Dominio Pirina 3 de la Familia NLR Límite: Humans Idioma: En Revista: Cell Año: 2017 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos