A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production

Ueli Nachbur, Che A. Stafford, Aleksandra Bankovacki, Yifan Zhan, Lisa M Lindqvist, Berthe K. Fiil, Yelena Khakham, Hyun-Ja Ko, Jarrod J Sandow, Hendrik Falk, Jessica K. Holien, Diep Chau, Joanne Hildebrand, James E Vince, Phillip P Sharp, Andrew I. Webb, Katherine A. Jackman, Sabrina Mühlen, Catherine L. Kennedy, Kym N Lowes & 8 others James M. Murphy, Mads Gyrd-Hansen, Michael W. Parker, Elizabeth L. Hartland, Andrew M Lew, David C S Huang, Guillaume Lessene, John Silke

Research output: Contribution to journalArticleResearchpeer-review

45 Citations (Scopus)

Abstract

Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-κB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.

Original languageEnglish
Article number6442
Number of pages13
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 17 Mar 2015
Externally publishedYes

Cite this

Nachbur, U., Stafford, C. A., Bankovacki, A., Zhan, Y., Lindqvist, L. M., Fiil, B. K., ... Silke, J. (2015). A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. Nature Communications, 6, [6442]. https://doi.org/10.1038/ncomms7442
Nachbur, Ueli ; Stafford, Che A. ; Bankovacki, Aleksandra ; Zhan, Yifan ; Lindqvist, Lisa M ; Fiil, Berthe K. ; Khakham, Yelena ; Ko, Hyun-Ja ; Sandow, Jarrod J ; Falk, Hendrik ; Holien, Jessica K. ; Chau, Diep ; Hildebrand, Joanne ; Vince, James E ; Sharp, Phillip P ; Webb, Andrew I. ; Jackman, Katherine A. ; Mühlen, Sabrina ; Kennedy, Catherine L. ; Lowes, Kym N ; Murphy, James M. ; Gyrd-Hansen, Mads ; Parker, Michael W. ; Hartland, Elizabeth L. ; Lew, Andrew M ; Huang, David C S ; Lessene, Guillaume ; Silke, John. / A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. In: Nature Communications. 2015 ; Vol. 6.
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abstract = "Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-κB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.",
author = "Ueli Nachbur and Stafford, {Che A.} and Aleksandra Bankovacki and Yifan Zhan and Lindqvist, {Lisa M} and Fiil, {Berthe K.} and Yelena Khakham and Hyun-Ja Ko and Sandow, {Jarrod J} and Hendrik Falk and Holien, {Jessica K.} and Diep Chau and Joanne Hildebrand and Vince, {James E} and Sharp, {Phillip P} and Webb, {Andrew I.} and Jackman, {Katherine A.} and Sabrina M{\"u}hlen and Kennedy, {Catherine L.} and Lowes, {Kym N} and Murphy, {James M.} and Mads Gyrd-Hansen and Parker, {Michael W.} and Hartland, {Elizabeth L.} and Lew, {Andrew M} and Huang, {David C S} and Guillaume Lessene and John Silke",
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Nachbur, U, Stafford, CA, Bankovacki, A, Zhan, Y, Lindqvist, LM, Fiil, BK, Khakham, Y, Ko, H-J, Sandow, JJ, Falk, H, Holien, JK, Chau, D, Hildebrand, J, Vince, JE, Sharp, PP, Webb, AI, Jackman, KA, Mühlen, S, Kennedy, CL, Lowes, KN, Murphy, JM, Gyrd-Hansen, M, Parker, MW, Hartland, EL, Lew, AM, Huang, DCS, Lessene, G & Silke, J 2015, 'A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production', Nature Communications, vol. 6, 6442. https://doi.org/10.1038/ncomms7442

A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. / Nachbur, Ueli; Stafford, Che A.; Bankovacki, Aleksandra; Zhan, Yifan; Lindqvist, Lisa M; Fiil, Berthe K.; Khakham, Yelena; Ko, Hyun-Ja; Sandow, Jarrod J; Falk, Hendrik; Holien, Jessica K.; Chau, Diep; Hildebrand, Joanne ; Vince, James E; Sharp, Phillip P; Webb, Andrew I.; Jackman, Katherine A.; Mühlen, Sabrina; Kennedy, Catherine L.; Lowes, Kym N; Murphy, James M.; Gyrd-Hansen, Mads; Parker, Michael W.; Hartland, Elizabeth L.; Lew, Andrew M; Huang, David C S; Lessene, Guillaume; Silke, John.

In: Nature Communications, Vol. 6, 6442, 17.03.2015.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Nachbur, Ueli

AU - Stafford, Che A.

AU - Bankovacki, Aleksandra

AU - Zhan, Yifan

AU - Lindqvist, Lisa M

AU - Fiil, Berthe K.

AU - Khakham, Yelena

AU - Ko, Hyun-Ja

AU - Sandow, Jarrod J

AU - Falk, Hendrik

AU - Holien, Jessica K.

AU - Chau, Diep

AU - Hildebrand, Joanne

AU - Vince, James E

AU - Sharp, Phillip P

AU - Webb, Andrew I.

AU - Jackman, Katherine A.

AU - Mühlen, Sabrina

AU - Kennedy, Catherine L.

AU - Lowes, Kym N

AU - Murphy, James M.

AU - Gyrd-Hansen, Mads

AU - Parker, Michael W.

AU - Hartland, Elizabeth L.

AU - Lew, Andrew M

AU - Huang, David C S

AU - Lessene, Guillaume

AU - Silke, John

PY - 2015/3/17

Y1 - 2015/3/17

N2 - Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-κB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.

AB - Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-κB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.

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DO - 10.1038/ncomms7442

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JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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Nachbur U, Stafford CA, Bankovacki A, Zhan Y, Lindqvist LM, Fiil BK et al. A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. Nature Communications. 2015 Mar 17;6. 6442. https://doi.org/10.1038/ncomms7442