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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 6442 (Mar 17 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25778803 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• NF-kappa B
• Recombinant Proteins
• Ubiquitin
• Interferon-gamma
• Adenosine Triphosphate
• RIPK2 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinase 2
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk2 protein, mouse

Topics

• Adenosine Triphosphate (chemistry)
• Animals
• Chromatography, Liquid
• Cytokines (metabolism)
• Encephalomyelitis, Autoimmune, Experimental (genetics)
• Female
• Humans
• Immune System
• Inflammation (metabolism)
• Inhibitory Concentration 50
• Interferon-gamma (metabolism)
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• NF-kappa B (metabolism)
• Protein Binding
• Protein Conformation
• Receptor-Interacting Protein Serine-Threonine Kinase 2 (antagonists & inhibitors, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Recombinant Proteins (metabolism)
• Signal Transduction
• Tandem Mass Spectrometry
• Ubiquitin (metabolism)