Th109 - Regulatory Role of JAK-1 Signaling in the Pathogenesis of Psoriatic Disease

Abstract Text: In psoriasis/psoriatic arthritis (PsA) there is aberrant activation of specific T cell subpopulations (Th17/Th9/MAIT cells). Homing of T cells in skin/ joints induce plaque and pannus formation by secreting cytokines through JAK/STAT signaling pathway. New generation JAK-1 inhibitors such as upadacitinib/filgotinib have demonstrated clinical efficacy in psoriatic disease with less adverse effect. Role of JAK-1 in pathogenesis of psoriatic disease remains unaddressed. IL-2/IL-9/IL-22 are known to recruit JAK-1 and play critical role in pathogenesis of PsA. In cultured FLS (synovial cells) and KC (keratinocytes), rIL-22 induced increased phosphorylation of JAK-1 compared to the culture media (p < 0.01); further we observed (i) FLS proliferation and IL-6, IL-8 and MMP-3 production by FLS are induced by rIL-22 (ii) rIL-22 induced significant increase in proliferation of NHEKs compared to media only ( < 0.005). KC/FLS pre-treated with upadacitinib had significantly lower proliferation than cells not pre-treated with upadacitinib at concentrations 1 μM and 5 μM ( < 0.01). rIL-2 and rIL-9 upregulated the expression of phospho-Jak1 in the PBMC T cells by 2-fold (p < 0.001) as compared to the untreated control. rIL-2 and rIL-9 induced significant proliferation in PsA PBMCs compared to unstimulated PBMCs (p < 0.001). The rIL-2/rIL-9 induced proliferation of PsA PBMC T cells could be significantly inhibited by upadacitinib at 1μM concentration (p < 0.01).
This study provides a novel insight about and independent role for JAK-1 signaling on (i) T cell dysregulation (ii) pannus and (iii) plaque formation in psoriatic disease and provides the mechanisms of actions JAK-1 inhibitor (upadacitinib) in the treatment of psoriasis and psoriatic arthritis.