@article{1801396150e94f56ae4bbeda969163af,
title = "Itaconate confers tolerance to late NLRP3 inflammasome activation",
abstract = "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.",
keywords = "immunometabolism, inflammasome, innate immunity, itaconate, macrophages",
author = "Monika Bambouskova and Lucie Potuckova and Tomas Paulenda and Martina Kerndl and Mogilenko, {Denis A.} and Kate Lizotte and Amanda Swain and Sebastian Hayes and Sheldon, {Ryan D.} and Hyeryun Kim and Unnati Kapadnis and Ellis, {Abigail E.} and Christine Isaguirre and Samantha Burdess and Anwesha Laha and Amarasinghe, {Gaya K.} and Victor Chubukov and Roddy, {Thomas P.} and Diamond, {Michael S.} and Jones, {Russell G.} and Simons, {Donald M.} and Artyomov, {Maxim N.}",
note = "Funding Information: We thank Laura Arthur and Alexandra Panteleeva for technical support; Prabhakar Sairam Andhey for help with data handling; Eyal Gottlieb, Henry D{\"a}britz, and Vicky Lampropoulou for help with Sdhb fl/fl mice; and Tsonwin Hai and Justin D. Middleton for providing Atf3 −/− mice. The work was supported by grant R01-AI125618 to M.N.A. from the National Institutes of Health , USA. Funding Information: We thank Laura Arthur and Alexandra Panteleeva for technical support; Prabhakar Sairam Andhey for help with data handling; Eyal Gottlieb, Henry D?britz, and Vicky Lampropoulou for help with Sdhbfl/fl mice; and Tsonwin Hai and Justin D. Middleton for providing Atf3?/? mice. The work was supported by grant R01-AI125618 to M.N.A. from the National Institutes of Health, USA. 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. K.L. S.H. H.K. U.K. V.C. T.P.R. and D.M.S. are employees of Agios Pharmaceuticals. M.S.D. is a consultant for Inbios, Eli Lilly, Vir Biotechnology, and NGM Biopharmaceuticals; is on the Scientific Advisory Board of Moderna; and has received laboratory funding under unrelated sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions. All other authors declare no competing financial interest. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = mar,
day = "9",
doi = "10.1016/j.celrep.2021.108756",
language = "English",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
number = "10",
}