Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation

Victoria A. McGuire, Tamara Ruiz-Zorrilla Diez, Christoph H. Emmerich, Sam Strickson, Maria Stella Ritorto, Ruhcha V. Sutavani, Anne Weiβ, Kirsty F. Houslay, Axel Knebel, Paul J. Meakin, Iain R. Phair, Michael L. J. Ashford, Matthias Trost, J. Simon C. Arthur (Lead / Corresponding author)

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Abstract

Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFκB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity.

Original languageEnglish
Article number31159
Pages (from-to)1-17
Number of pages17
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 8 Aug 2016

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Ubiquitin
Cytokines
Oxidants
Polyubiquitin
Autoimmunity
Psoriasis
Multiple Sclerosis
Anti-Inflammatory Agents
Dimethyl Fumarate
Enzymes
Pharmaceutical Preparations

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McGuire, V. A., Ruiz-Zorrilla Diez, T., Emmerich, C. H., Strickson, S., Ritorto, M. S., Sutavani, R. V., ... Arthur, J. S. C. (2016). Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Scientific Reports, 6, 1-17. [31159]. https://doi.org/10.1038/srep31159
McGuire, Victoria A. ; Ruiz-Zorrilla Diez, Tamara ; Emmerich, Christoph H. ; Strickson, Sam ; Ritorto, Maria Stella ; Sutavani, Ruhcha V. ; Weiβ, Anne ; Houslay, Kirsty F. ; Knebel, Axel ; Meakin, Paul J. ; Phair, Iain R. ; Ashford, Michael L. J. ; Trost, Matthias ; Arthur, J. Simon C. / Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. In: Scientific Reports. 2016 ; Vol. 6. pp. 1-17.
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abstract = "Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFκB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity.",
author = "McGuire, {Victoria A.} and {Ruiz-Zorrilla Diez}, Tamara and Emmerich, {Christoph H.} and Sam Strickson and Ritorto, {Maria Stella} and Sutavani, {Ruhcha V.} and Anne Weiβ and Houslay, {Kirsty F.} and Axel Knebel and Meakin, {Paul J.} and Phair, {Iain R.} and Ashford, {Michael L. J.} and Matthias Trost and Arthur, {J. Simon C.}",
note = "This work was supported by grants from Arthritis Research UK and the Medical Research Council and by AstraZeneca, BoehringerIngelheim, GlaxoSmithKline, Merck KGaA, Janssen Pharmaceutica via their support for the DSTT consortium in Dundee",
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Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. / McGuire, Victoria A.; Ruiz-Zorrilla Diez, Tamara; Emmerich, Christoph H.; Strickson, Sam; Ritorto, Maria Stella; Sutavani, Ruhcha V.; Weiβ, Anne; Houslay, Kirsty F.; Knebel, Axel; Meakin, Paul J.; Phair, Iain R.; Ashford, Michael L. J.; Trost, Matthias; Arthur, J. Simon C. (Lead / Corresponding author).

In: Scientific Reports, Vol. 6, 31159, 08.08.2016, p. 1-17.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation

AU - McGuire, Victoria A.

AU - Ruiz-Zorrilla Diez, Tamara

AU - Emmerich, Christoph H.

AU - Strickson, Sam

AU - Ritorto, Maria Stella

AU - Sutavani, Ruhcha V.

AU - Weiβ, Anne

AU - Houslay, Kirsty F.

AU - Knebel, Axel

AU - Meakin, Paul J.

AU - Phair, Iain R.

AU - Ashford, Michael L. J.

AU - Trost, Matthias

AU - Arthur, J. Simon C.

N1 - This work was supported by grants from Arthritis Research UK and the Medical Research Council and by AstraZeneca, BoehringerIngelheim, GlaxoSmithKline, Merck KGaA, Janssen Pharmaceutica via their support for the DSTT consortium in Dundee

PY - 2016/8/8

Y1 - 2016/8/8

N2 - Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFκB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity.

AB - Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFκB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity.

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DO - 10.1038/srep31159

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C2 - 27498693

VL - 6

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EP - 17

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 31159

ER -

McGuire VA, Ruiz-Zorrilla Diez T, Emmerich CH, Strickson S, Ritorto MS, Sutavani RV et al. Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Scientific Reports. 2016 Aug 8;6:1-17. 31159. https://doi.org/10.1038/srep31159