Journal Article

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

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

2015

Overview

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. Receptor Interacting Protein Kinase 2 (RIPK2) mediates innate immune signalling in response to intracellular pathogens, but its aberrant activation contributes to autoimmune pathologies. Here Nachbur et al. describe a RIPK2 inhibitor that is effective in a mouse model of multiple sclerosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/21 / 631/250/249/2510 / 631/250/262/2106/2517 / 631/80/86 / 64/60 / 692/700/565 / 82 / 82/58 / 96 / 96/95 / 96/98 / Adenosine / Adenosine Triphosphate - chemistry / Amino acids / Animals / Biology / Chromatography, Liquid / Cytokines / Cytokines - metabolism / Disease / Encephalomyelitis, Autoimmune, Experimental - genetics / Female / Humanities and Social Sciences / Humans / Immune System / Inflammation - metabolism / Inhibitory Concentration 50 / Interferon-gamma - metabolism / Kinases / Male / MAP Kinase Signaling System / Medical research / Mice / Mice, Inbred C57BL / Mice, Inbred NOD / multidisciplinary / NF-kappa B - metabolism / Phosphorylation / Protein Binding / Protein Conformation / Proteins / Receptor-Interacting Protein Serine-Threonine Kinase 2 - antagonists & inhibitors / Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism / Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Recombinant Proteins - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Tandem Mass Spectrometry / Ubiquitin - metabolism