712 Comparing RNAseq analysis of the mouse IL-23 minicircle model to human psoriasis and other preclinical models of skin inflammation

Abstract

Hydrodynamic delivery of a single i.v. injection of IL-23 minicircles (MC) in male B10. RIII mice induces psoriasiform dermatitis. To further evaluate its similarity to human psoriasis, RNAseq was performed and the data used for pathway analysis. Injection of 3 μg IL-23 MC induced ear skin inflammation, and elevation of key IL-23/IL-17 pathway cytokines/chemokines over an 11 day study. The RNAseq analyses from MC mice revealed that 15 of the top 20 affected pathways were also amongst the top 20 pathways identified in human psoriasis (Li et al., 2014) including those related to the IL-17A/F pathways. Additional associations within the top 20 pathways for the MC model included neuroinflammation, IL-10 signaling, and dendritic cell maturation pathways. When comparing human alignment of the MC model to an IL-23 ear injection (4 daily injections) and other preclinical psoriasis models, including IMQ, both IL-23 models show the strongest alignment to human psoriasis. The MC model tended to have a more amplified signal compared to the IL-23 ear injection model. Shams in the IL-23 ear injection model also had transcriptome changes which are not typical of psoriasis nor found in the MC shams, and may have been related to needle stick injury. The type I interferon pathway was under represented in both IL-23 models relative to human psoriasis. Most upstream regulators were shared between human psoriasis and the MC model, and also to the IL-23 ear injection model, but to a lesser degree. Treatment with apremilast, as well as anti-IL-23p40, anti-IL-23p19, or anti-TNF mAbs suppressed most of the gene changes in the MC model. In summary, both IL-23 models align more closely with human psoriasis than other preclinical models reported in the literature. The IL-23 MC tends to have a more amplified signal of these key pathways relative to the IL-23 ear injection model, and does not induce changes that seem to be associated with needle stick injury.