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 and John Silke ()
Additional contact information
Ueli Nachbur: The Walter and Eliza Hall Institute of Medical Research
Che A. Stafford: The Walter and Eliza Hall Institute of Medical Research
Aleksandra Bankovacki: The Walter and Eliza Hall Institute of Medical Research
Yifan Zhan: The Walter and Eliza Hall Institute of Medical Research
Lisa M. Lindqvist: The Walter and Eliza Hall Institute of Medical Research
Berthe K. Fiil: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Yelena Khakham: The Walter and Eliza Hall Institute of Medical Research
Hyun-Ja Ko: The Walter and Eliza Hall Institute of Medical Research
Jarrod J. Sandow: The Walter and Eliza Hall Institute of Medical Research
Hendrik Falk: The Walter and Eliza Hall Institute of Medical Research
Jessica K. Holien: ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research
Diep Chau: The Walter and Eliza Hall Institute of Medical Research
Joanne Hildebrand: The Walter and Eliza Hall Institute of Medical Research
James E. Vince: The Walter and Eliza Hall Institute of Medical Research
Phillip P. Sharp: The Walter and Eliza Hall Institute of Medical Research
Andrew I. Webb: The Walter and Eliza Hall Institute of Medical Research
Katherine A. Jackman: The Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Austin Campus
Sabrina Mühlen: University of Melbourne
Catherine L. Kennedy: University of Melbourne
Kym N. Lowes: The Walter and Eliza Hall Institute of Medical Research
James M. Murphy: The Walter and Eliza Hall Institute of Medical Research
Mads Gyrd-Hansen: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
Michael W. Parker: ACRF Rational Drug Discovery Centre, St Vincent’s Institute of Medical Research
Elizabeth L. Hartland: University of Melbourne
Andrew M. Lew: The Walter and Eliza Hall Institute of Medical Research
David C. S. Huang: The Walter and Eliza Hall Institute of Medical Research
Guillaume Lessene: The Walter and Eliza Hall Institute of Medical Research
John Silke: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7442

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DOI: 10.1038/ncomms7442

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