Short-term IL-23 neutralization reduces IL-23 transcription and number of activated pro-inflammatory mononuclear phagocyte (MNPs) in psoriasis skin ex vivo

In psoriasis, inflammatory signaling in the skin is primarily driven by the interleukin (IL)-23/Th17 axis. Systemic blockade of IL-23 in psoriasis patients has led to high levels of clinical response, accompanied by reduced frequencies of pro-inflammatory CD11c+CD14brightCD64bright monocyte-like cells, the main producers of IL-23 within mononuclear phagocyte (MNP) infiltrates in psoriatic lesions. Yet, how IL-23 blockade regulates MNPs remains unclear. To study this, we treated full-thickness human lesional and peri-lesional psoriatic skin with an anti-IL23p19 subunit mAb for up to 72h ex vivo. The psoriatic phenotype was maintained during organ culture, as confirmed by demonstrating significantly higher numbers of CD3+IL-17A+, CD14+CD11c+, and CD14-CD11c+ cells in lesional versus peri-lesional skin, and release of IL-17A, CCL20, IL-1β, and β-defensin-2 into the medium. RNAseq analysis confirmed expression of the psoriatic transcriptomic signature in lesional compared to peri-lesional skin; this was partially corrected by IL-23 blockade in lesional skin, as demonstrated by a trend towards down-regulation of select genes (e.g. IL17A, CCL20, IL1B, and IL36G). IL-23 blockade also led to a trend in reduction of IL-17A and significant reduction of the keratinocyte or myeloid cell-derived cytokines CCL20 and IL-1β. Importantly, neutralization of IL-23 in lesional skin resulted in decreased mRNA expression of IL23A, FCGR1A (CD64), CD40 and CD80, and reduction in the proportions of CD40+ and CD64+ cells among CD14-CD11c+ and CD14+CD11c+, but not CD14+CD11c- cells. In conclusion, short-term IL-23 blockade affects inflammatory MNP activities in a psoriasis skin explant model.