The potent and selective RIPK2 inhibitor BI 706039 improves intestinal inflammation in the TRUC mouse model of inflammatory bowel disease.

Mouse and human data implicate the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the receptor interacting protein kinase 2 (RIPK2) as a potential key signaling node for the development of inflammatory bowel disease (IBD) and an attractive target for pharmacological intervention. The TRUC mouse model of IBD was strongly indicated for evaluating RIPK2 antagonism for its effect on intestinal inflammation based on previous knockout studies with NOD1, NOD2, and RIPK2. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from age 28 to 56 days. Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight, and terminal levels of protein-normalized fecal lipocalin (all P values <0.001). These observations correlated with dose responsively increasing systemic levels of the BI 706039 compound, splenic molecular target engagement of RIPK2, and modulation of inflammatory genes in the colon. This demonstrates that a relatively low oral dose of a potent and selective RIPK2 inhibitor can modulate signaling in the intestinal immune system and significantly improve disease associated intestinal inflammation.NEW & NOTEWORTHY The RIPK2 kinase at the apex of microbiome immunosensing is an attractive target for pharmacological intervention. A low oral dose of a RIPK2 inhibitor leads to significantly improved intestinal inflammation in the murine TRUC model of colitis. A selective and potent inhibitor of the RIPK2 kinase may represent a new class of therapeutics that target microbiome-driven signaling for the treatment of IBD.

The impact of genetic background and sex on the phenotype of IL-23 induced murine spondyloarthritis.

BACKGROUND: Overexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated. METHODS: We compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8-12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA. FINDINGS: Male B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight. CONCLUSIONS: The phenotype of IL-23 induced disease in mice is controlled by genetic background and sex of the animals. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests that organ-specificity of IL-23 driven inflammation is genetically determined. The mechanisms behind the strain-specific differences and the sexual dimorphism observed in this study may be relevant for human spondyloarthritis and warrant further exploration.