Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation
Wei Wang,
Alesja Dernst,
Bianca Martin,
Lucia Lorenzi,
Maria Cadefau-Fabregat,
Kshiti Phulphagar,
Antonia Wagener,
Christina Budden,
Neil Stair,
Theresa Wagner,
Harald Färber,
Andreas Jaensch,
Rainer Stahl,
Fraser Duthie,
Susanne V. Schmidt,
Rebecca C. Coll,
Felix Meissner,
Sergi Cuartero,
Eicke Latz,
Matthew S.J. Mangan
Affiliations
Wei Wang
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7BL, UK
Alesja Dernst
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Bianca Martin
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Lucia Lorenzi
Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Barcelona, Spain
Maria Cadefau-Fabregat
Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Barcelona, Spain
Kshiti Phulphagar
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Antonia Wagener
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Christina Budden
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Neil Stair
Institute for Genetics, CECAD Research Center, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Theresa Wagner
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Harald Färber
Institute for Hygiene and Public Health, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Andreas Jaensch
Institute for Hygiene and Public Health, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Rainer Stahl
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Fraser Duthie
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Susanne V. Schmidt
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Rebecca C. Coll
Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7BL, UK
Felix Meissner
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
Sergi Cuartero
Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Barcelona, Spain
Eicke Latz
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases, 53127 Bonn, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA; Deutsches Rheuma Forschungszentrum Berlin (DRFZ), 10117 Berlin, Germany; Corresponding author
Matthew S.J. Mangan
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases, 53127 Bonn, Germany; Corresponding author
Summary: Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.
