Session Type: Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Receptor interacting protein kinase 2 (RIPK2) is a key signaling node for inflammation caused by peptidoglycan (PGN). In the intestine, RIPK2 integrates signaling originating from the microbiota and amplifies pro-inflammatory responses. Hence, blocking RIPK2 is an attractive strategy to treat inflammatory bowel disease. Since peptidoglycan is present in the serum and joints in patients with rheumatic diseases and is thought to drive sterile inflammation, RIPK2 inhibitors may also be a novel approach to treat rheumatoid arthritis, osteoarthritis, and spondyloarthritis. While the kinase function of RIPK2 is dispensable for downstream signaling, its ability to recruit and activate the E3 ubiquitin ligase, XIAP, is critical for RIPK2 ubiquitination and signal transduction. On this basis, we developed a RIPK2 scaffolding inhibitor that binds to RIPK2, prevents interaction with XIAP, and blocks proinflammatory responses in vitro and in vivo.
Methods: Direct inhibition of RIPK2 scaffolding with XIAP was demonstrated using surface plasmon resonance and a cellular nanoBRET assay. Inhibitory activity was evaluated by NF-kB dependent gene expression in NOD1 and NOD2 reporter cell lines and cytokine production in primary human cells stimulated with PGN fragments or Toll like receptor (TLR) ligands. Potency and selectivity was compared to GSK-559, a RIPK2 kinase inhibitor, and efficacy of the Odyssey RIPK2 scaffolding inhibitor in vivo was evaluated in a PGN-challenge mouse model.
Results: RIPK2 scaffolding inhibitor blocks the binding of recombinant XIAP with RIPK2 in vitro and in cells. RIPK2 scaffolding inhibitor blocks MAPK pathway activation, NF-kB activation, and cytokine production (e.g., TNF, IL-23, and TL1A) in human monocytes and macrophages stimulated with PGN fragments, but not TLR ligands. We observed a synergistic cytokine response in human monocytes stimulated by both NOD1/2 and TLR ligands. This synergistic response is blocked by treatment with a scaffolding inhibitor, but not a RIPK2 kinase inhibitor. Oral administration of the RIPK2 scaffolding inhibitor dose-dependently reduced production of TNF, IL-6, and MCP-1 in response to PGN.
Conclusion: We describe a potent and selective RIPK2 scaffolding inhibitor and demonstrate that blocking scaffolding is necessary to maximally inhibit RIPK2 activation in response to the microbiota. These data show the therapeutic potential of using a RIPK2 scaffolding inhibitor to prevent pathogenic responses to microbiota from which inflammatory intestinal and rheumatic diseases originate.
To cite this abstract in AMA style:Wlodarska M, Van Huis C, Hoss F, Meyer R, Lu X, Koelmel D, Sanchez B, Lesch C, Telling A, Minns M, Mbah N, Lacan I, Aversa R, Lesburg C, Yu C, Soisson S, Dales N, Patrick D, Opipari A, Pan S, Franchi L. Discovery of a RIPK2 Scaffolding Inhibitor for the Treatment of Joint Autoimmune Diseases [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/discovery-of-a-ripk2-scaffolding-inhibitor-for-the-treatment-of-joint-autoimmune-diseases/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-of-a-ripk2-scaffolding-inhibitor-for-the-treatment-of-joint-autoimmune-diseases/