Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

Evanna L. Mills, Dylan G. Ryan, Hiran A. Prag, Dina Dikovskaya, Deepthi Menon, Zbigniew Zaslona, Mark P. Jedrychowski, Ana S. H. Costa, Maureen Higgins, Emily Hams, John Szpyt, Marah C. Runtsch, Martin S. King, Joanna F. McGouran, Roman Fischer, Benedikt M. Kessler, Anne F. McGettrick, Mark M. Hughes, Richard G. Carroll, Lee M. BootyElena V. Knatko, Paul J. Meakin, Michael L. J. Ashford, Louise K. Modis, Gino Brunori, Daniel C. Sévin, Padraic G. Fallon, Stuart T. Caldwell, Edmund R. S. Kunji, Edward T. Chouchani, Christian Frezza, Albena T. Dinkova-Kostova, Richard C. Hartley, Michael P. Murphy, Luke A. O'Neill

Research output: Contribution to journalArticle

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Abstract

The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.

Original languageEnglish
Pages (from-to)113-117
Number of pages5
JournalNature
Volume556
Issue number7699
Early online date28 Mar 2018
DOIs
Publication statusPublished - 5 Apr 2018

Fingerprint

Alkylation
Anti-Inflammatory Agents
Interferon Type I
Cysteine
Lipopolysaccharides
itaconic acid
Macrophages
Oxidants
Interferons
Transcription Factors
Cytokines
Inflammation
Gene Expression

Keywords

  • Metabolomics
  • Monocytes and macrophages
  • Sepsis

Cite this

Mills, E. L., Ryan, D. G., Prag, H. A., Dikovskaya, D., Menon, D., Zaslona, Z., ... O'Neill, L. A. (2018). Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature, 556(7699), 113-117. https://doi.org/10.1038/nature25986
Mills, Evanna L. ; Ryan, Dylan G. ; Prag, Hiran A. ; Dikovskaya, Dina ; Menon, Deepthi ; Zaslona, Zbigniew ; Jedrychowski, Mark P. ; Costa, Ana S. H. ; Higgins, Maureen ; Hams, Emily ; Szpyt, John ; Runtsch, Marah C. ; King, Martin S. ; McGouran, Joanna F. ; Fischer, Roman ; Kessler, Benedikt M. ; McGettrick, Anne F. ; Hughes, Mark M. ; Carroll, Richard G. ; Booty, Lee M. ; Knatko, Elena V. ; Meakin, Paul J. ; Ashford, Michael L. J. ; Modis, Louise K. ; Brunori, Gino ; Sévin, Daniel C. ; Fallon, Padraic G. ; Caldwell, Stuart T. ; Kunji, Edmund R. S. ; Chouchani, Edward T. ; Frezza, Christian ; Dinkova-Kostova, Albena T. ; Hartley, Richard C. ; Murphy, Michael P. ; O'Neill, Luke A. / Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. In: Nature. 2018 ; Vol. 556, No. 7699. pp. 113-117.
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abstract = "The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.",
keywords = "Metabolomics, Monocytes and macrophages , Sepsis",
author = "Mills, {Evanna L.} and Ryan, {Dylan G.} and Prag, {Hiran A.} and Dina Dikovskaya and Deepthi Menon and Zbigniew Zaslona and Jedrychowski, {Mark P.} and Costa, {Ana S. H.} and Maureen Higgins and Emily Hams and John Szpyt and Runtsch, {Marah C.} and King, {Martin S.} and McGouran, {Joanna F.} and Roman Fischer and Kessler, {Benedikt M.} and McGettrick, {Anne F.} and Hughes, {Mark M.} and Carroll, {Richard G.} and Booty, {Lee M.} and Knatko, {Elena V.} and Meakin, {Paul J.} and Ashford, {Michael L. J.} and Modis, {Louise K.} and Gino Brunori and S{\'e}vin, {Daniel C.} and Fallon, {Padraic G.} and Caldwell, {Stuart T.} and Kunji, {Edmund R. S.} and Chouchani, {Edward T.} and Christian Frezza and Dinkova-Kostova, {Albena T.} and Hartley, {Richard C.} and Murphy, {Michael P.} and O'Neill, {Luke A.}",
note = "We thank M. McMahon and J. D. Hayes for plasmids, and Cancer Research UK (C20953/A18644) and the BBSRC (BB/L01923X/1) for financial support for ATDK. This work was supported by a Wellcome Trust Investigator award to R.C.H. (110158/Z/15/Z), a grant to M.P.M. from the Medical Research Council UK (MC_U105663142), a Wellcome Trust Investigator award to MPM (110159/Z/15/Z), and a grant to E.R.S.K. and M.S.K. from the Medical Research Council UK (MC_U105663139). B.M.K. and R.F. are supported by the Kennedy Trust Fund. We acknowledge Metabolon for their assistance with the metabolic work and analysis. The O’Neill laboratory acknowledges the following grant support: European Research Council (ECFP7-ERC-MICROINNATE), Science Foundation Ireland Investigator Award (SFI 12/IA/1531), GlaxoSmithKline Visiting Scientist Programme and The Wellcome Trust (oneill-wellcometrust-metabolic, grant number 205455). E.T.C. is supported by the Claudia Adams Barr Program.",
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Mills, EL, Ryan, DG, Prag, HA, Dikovskaya, D, Menon, D, Zaslona, Z, Jedrychowski, MP, Costa, ASH, Higgins, M, Hams, E, Szpyt, J, Runtsch, MC, King, MS, McGouran, JF, Fischer, R, Kessler, BM, McGettrick, AF, Hughes, MM, Carroll, RG, Booty, LM, Knatko, EV, Meakin, PJ, Ashford, MLJ, Modis, LK, Brunori, G, Sévin, DC, Fallon, PG, Caldwell, ST, Kunji, ERS, Chouchani, ET, Frezza, C, Dinkova-Kostova, AT, Hartley, RC, Murphy, MP & O'Neill, LA 2018, 'Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1', Nature, vol. 556, no. 7699, pp. 113-117. https://doi.org/10.1038/nature25986

Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. / Mills, Evanna L.; Ryan, Dylan G.; Prag, Hiran A.; Dikovskaya, Dina; Menon, Deepthi; Zaslona, Zbigniew; Jedrychowski, Mark P.; Costa, Ana S. H.; Higgins, Maureen; Hams, Emily; Szpyt, John; Runtsch, Marah C.; King, Martin S.; McGouran, Joanna F.; Fischer, Roman; Kessler, Benedikt M.; McGettrick, Anne F.; Hughes, Mark M.; Carroll, Richard G.; Booty, Lee M.; Knatko, Elena V.; Meakin, Paul J.; Ashford, Michael L. J.; Modis, Louise K.; Brunori, Gino; Sévin, Daniel C.; Fallon, Padraic G.; Caldwell, Stuart T.; Kunji, Edmund R. S.; Chouchani, Edward T.; Frezza, Christian; Dinkova-Kostova, Albena T.; Hartley, Richard C.; Murphy, Michael P.; O'Neill, Luke A. (Lead / Corresponding author).

In: Nature, Vol. 556, No. 7699, 05.04.2018, p. 113-117.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

AU - Mills, Evanna L.

AU - Ryan, Dylan G.

AU - Prag, Hiran A.

AU - Dikovskaya, Dina

AU - Menon, Deepthi

AU - Zaslona, Zbigniew

AU - Jedrychowski, Mark P.

AU - Costa, Ana S. H.

AU - Higgins, Maureen

AU - Hams, Emily

AU - Szpyt, John

AU - Runtsch, Marah C.

AU - King, Martin S.

AU - McGouran, Joanna F.

AU - Fischer, Roman

AU - Kessler, Benedikt M.

AU - McGettrick, Anne F.

AU - Hughes, Mark M.

AU - Carroll, Richard G.

AU - Booty, Lee M.

AU - Knatko, Elena V.

AU - Meakin, Paul J.

AU - Ashford, Michael L. J.

AU - Modis, Louise K.

AU - Brunori, Gino

AU - Sévin, Daniel C.

AU - Fallon, Padraic G.

AU - Caldwell, Stuart T.

AU - Kunji, Edmund R. S.

AU - Chouchani, Edward T.

AU - Frezza, Christian

AU - Dinkova-Kostova, Albena T.

AU - Hartley, Richard C.

AU - Murphy, Michael P.

AU - O'Neill, Luke A.

N1 - We thank M. McMahon and J. D. Hayes for plasmids, and Cancer Research UK (C20953/A18644) and the BBSRC (BB/L01923X/1) for financial support for ATDK. This work was supported by a Wellcome Trust Investigator award to R.C.H. (110158/Z/15/Z), a grant to M.P.M. from the Medical Research Council UK (MC_U105663142), a Wellcome Trust Investigator award to MPM (110159/Z/15/Z), and a grant to E.R.S.K. and M.S.K. from the Medical Research Council UK (MC_U105663139). B.M.K. and R.F. are supported by the Kennedy Trust Fund. We acknowledge Metabolon for their assistance with the metabolic work and analysis. The O’Neill laboratory acknowledges the following grant support: European Research Council (ECFP7-ERC-MICROINNATE), Science Foundation Ireland Investigator Award (SFI 12/IA/1531), GlaxoSmithKline Visiting Scientist Programme and The Wellcome Trust (oneill-wellcometrust-metabolic, grant number 205455). E.T.C. is supported by the Claudia Adams Barr Program.

PY - 2018/4/5

Y1 - 2018/4/5

N2 - The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.

AB - The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.

KW - Metabolomics

KW - Monocytes and macrophages

KW - Sepsis

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VL - 556

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JO - Nature

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