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.
Highlights
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-kB and MAP kinases
NOD signalling leads to the activation of NF-kB and MAP kinases resulting in the transcription of pro-inflammatory cytokines[12], as well as the induction of autophagy[13]
We and others have shown that upon NOD stimulation, Receptor interacting protein kinase 2 (RIPK2) is ubiquitylated by inhibitor of apoptosis (IAP) proteins, and this recruits the linear ubiquitination assembly complex (LUBAC), which is essential for downstream signalling[16,17,18]
Summary
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-kB and MAP kinases. We develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-kB activation downstream of NOD engagement. Pharmacological inhibition of RIPK2 kinase activity via these relatively nonspecific inhibitors caused a reduction in RIPK2 stability and a reduction in cytokine production upon NOD stimulation. These inhibitors inhibit other kinases in the NOD signalling pathway to varying degrees; it is difficult to distinguish RIPK2-specific effects. To better understand the role of the kinase activity of RIPK2 in NOD signalling and to explore RIPK2 as a potential therapeutic target, we developed a specific and potent RIPK2 inhibitor and tested it in vitro and in vivo
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