title: Aging-Associated TNF Production Primes Inflammasome Activation and NLRP3-Related Metabolic Disturbances.
abstract: Accumulating evidence suggests that the activation of the innate branch of the immune system plays a pivotal role in the induction and perpetuation of metabolic and aging-related diseases. In this context, the NLRP3 inflammasome pathway has been identified as an important driver of sterile inflammatory processes. De novo protein synthesis of NLRP3 induced by signals such as TLR ligands or TNF is a prerequisite for sustained NLRP3 mediated caspase-1 cleavage and inflammasome activation. Here, we demonstrate in aged mice that spontaneously elevated TNF represents a critical priming signal that functions to control NLRP3 inflammasome activation. Elevated systemic TNF levels were responsible for increased NLRP3 expression and caspase-1 activity in adipose tissues and liver. TNF dependent, spontaneous inflammasome activity in aged mice resulted in impaired glucose tolerance that could be attributed to peripheral insulin resistance. Altogether, these results implicate that TNF-driven NLRP3 expression constitutes an important checkpoint that regulates inflammasome activation, presumably by additional signals such as aging-associated DAMPs.
authors: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany; Department of Internal Medicine III, University Hospital, University of Bonn, 53127 Bonn, Germany; bauernfeind@uni-bonn.de veit.hornung@uni-bonn.de.
authors: Franz
authors: F
authors: Bauernfeind
authors: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors: Sven
authors: S
authors: Niepmann
authors: Institute of Experimental Immunology, University Hospital, University of Bonn, 53127 Bonn, Germany; Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, 81675 Munich, Germany; and.
authors: Percy A
authors: PA
authors: Knolle
authors: Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany; Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany bauernfeind@uni-bonn.de veit.hornung@uni-bonn.de.
authors: Veit
authors: V
authors: Hornung
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D005260:Female; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000096:biosynthesis*
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D048069:Tumor Necrosis Factors