Journal Article

DZNE-2024-01169

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation.

Wang, W. ; Dernst, A. ; Martin, B. ; Lorenzi, L. ; Cadefau-Fabregat, M. ; Phulphagar, K. ; Wagener, A. ; Budden, C. ; Stair, N. ; Wagner, T. ; Färber, H. ; Jaensch, A. ; Stahl, R. ; Duthie, F. ; Schmidt, S. V. ; Coll, R. C. ; Meissner, F. ; Cuartero, S. ; Latz, E.DZNE* ; Mangan, M. (Last author)DZNE*

2024
Elsevier [New York, NY]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2024.114736

Abstract: 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.

Keyword(s): Humans (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: metabolism (MeSH) ; Inflammasomes: metabolism (MeSH) ; Propionates: pharmacology (MeSH) ; Butyrates: pharmacology (MeSH) ; Macrophages: metabolism (MeSH) ; Macrophages: drug effects (MeSH) ; Toll-Like Receptors: metabolism (MeSH) ; Signal Transduction: drug effects (MeSH) ; Interleukin-1beta: metabolism (MeSH) ; Interleukin-10: metabolism (MeSH) ; CP: Immunology ; HDAC ; IL-10 ; NLRP3 ; SCFA ; acetylation ; butyrate ; cFLIP ; caspase-8 ; inflammasome ; propionate ; NLR Family, Pyrin Domain-Containing 3 Protein ; Inflammasomes ; Propionates ; Butyrates ; Toll-Like Receptors ; NLRP3 protein, human ; Interleukin-1beta ; Interleukin-10

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Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2024

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