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; James M Murphy; Mads Gyrd-Hansen; Michael W Parker; Elizabeth L Hartland; Andrew M Lew; David C S Huang; Guillaume Lessene; John Silke

doi:10.1038/ncomms7442

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 LowesJames M Murphy, Mads Gyrd-Hansen, Michael W Parker, Elizabeth L Hartland, Andrew M Lew, David C S Huang, Guillaume Lessene, John Silke

61 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 language	English
Article number	6442
Journal	Nature Communications
Volume	6
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms7442
Publication status	Published - 17 Mar 2015

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Nachbur, U., Stafford, C. A., Bankovacki, A., Zhan, Y., Lindqvist, L. M., Fiil, B. K., Khakham, Y., Ko, H-J., Sandow, J. J., Falk, H., Holien, J. K., Chau, D., Hildebrand, J., Vince, J. E., Sharp, P. P., Webb, A. I., Jackman, K. A., Mühlen, S., Kennedy, C. L., ... 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, 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

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title = "A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production",

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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T1 - A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production

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.

U2 - 10.1038/ncomms7442

DO - 10.1038/ncomms7442

M3 - Journal article

C2 - 25778803

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6442

ER -

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

Abstract

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