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

2015-03-17

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

Journal Article

10.1038/ncomms7442

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.

link

Nature Communications 2015; 6(): 6442

Nature Communications