Itaconate confers tolerance to late NLRP3 inflammasome activation

Itaconate is a unique regulatory metabolite that is induced upon Toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a ke...

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Veröffentlicht in:	Cell reports (Cambridge) Jg. 34; H. 10; S. 108756
Hauptverfasser:	Bambouskova, Monika, Potuckova, Lucie, Paulenda, Tomas, Kerndl, Martina, Mogilenko, Denis A., Lizotte, Kate, Swain, Amanda, Hayes, Sebastian, Sheldon, Ryan D., Kim, Hyeryun, Kapadnis, Unnati, Ellis, Abigail E., Isaguirre, Christine, Burdess, Samantha, Laha, Anwesha, Amarasinghe, Gaya K., Chubukov, Victor, Roddy, Thomas P., Diamond, Michael S., Jones, Russell G., Simons, Donald M., Artyomov, Maxim N.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Elsevier Inc 09.03.2021 Elsevier
Schlagworte:	Adenosine Triphosphate - pharmacology Animals Caspase 1 - metabolism Hydro-Lyases - deficiency Hydro-Lyases - genetics Hydro-Lyases - metabolism immunometabolism inflammasome Inflammasomes - drug effects Inflammasomes - metabolism innate immunity Interleukin-1beta - metabolism Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism itaconate Lipopolysaccharides - pharmacology macrophages Macrophages - cytology Macrophages - drug effects Macrophages - metabolism Mice Mice, Inbred C57BL Mice, Knockout Nitric Oxide Synthase Type II - metabolism NLR Family, Pyrin Domain-Containing 3 Protein - genetics NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Phosphate-Binding Proteins - genetics Phosphate-Binding Proteins - metabolism Poly I-C - pharmacology Pyroptosis - drug effects Sepsis - chemically induced Sepsis - metabolism Sepsis - pathology Signal Transduction - drug effects Succinates - pharmacology Toll-Like Receptors - chemistry Toll-Like Receptors - metabolism macrophages itaconate innate immunity immunometabolism inflammasome
ISSN:	2211-1247, 2211-1247
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Zusammenfassung:	Itaconate is a unique regulatory metabolite that is induced upon Toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a key regulator of the signal 2 of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation after long lipopolysaccharide (LPS) priming, which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with inducible nitric oxide synthase (iNOS) and that the ability of various TLR ligands to establish NLRP3 inflammasome tolerance depends on the pattern of co-expression of IRG1 and iNOS. Mechanistically, itaconate accumulation upon prolonged inflammatory stimulation prevents full caspase-1 activation and processing of gasdermin D, which we demonstrate to be post-translationally modified by endogenous itaconate. Altogether, our data demonstrate that metabolic rewiring in inflammatory macrophages establishes tolerance to NLRP3 inflammasome activation that, if uncontrolled, can result in pyroptotic cell death and tissue damage. [Display omitted] •Itaconate tolerizes macrophages to late NLRP3 inflammasome (i.e., long LPS priming)•Itaconate acts downstream of ASC, affecting caspase-1/GSDMD interplay•Late inflammasome require GSDMD for caspase-1 activation; GSDMD-Cys77 is itaconated•iNOS and IRG1 jointly establish late inflammasome tolerance Bambouskova et al. determine the in vitro phenotype of Irg1−/− macrophages and define itaconate as a key regulator of tolerance to late NLRP3 inflammasome activation.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS M.B. and M.N.A. conceived and designed the study and wrote the manuscript. M.B. performed cell-based biochemistry, cytokine detection, flow cytometry, enzyme activity measures, and data analysis. L.P. and T.P. performed in vivo endotoxic shock experiments and helped with experiments. M.K. performed in vivo psoriasis and flow cytometry analysis of tissue samples. D.A.M. and A.S. helped with experiments. K.L., S.H., H.K., U.K., V.C., and D.M.S. performed proteomic mass spectrometry. R.D.S., A.E.E., C.I., and R.G.J. performed metabolic mass spectrometry and data analysis. S.B. and A.L. helped with animal work. G.K.A. and M.S.D. contributed with animals and reagents.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2021.108756