Targeting inflammatory skin disease using a novel immune modulating agent

Abstract

Chronic inflammatory skin diseases such as psoriasis and atopic dermatitis (AD) are growing global health concerns and developing new therapeutics is much needed. RP23, a human self-derived peptide, has novel anti-inflammatory properties as an injected therapeutic in contact hypersensitivity and psoriasis mouse models. In this thesis, we have conducted further experiments to determine mechanistic insight of RP23 and optimised a topical therapy for its therapeutic use in inflammatory skin diseases. We found that murine BMDMs treated in vitro with RP23 had suppressed LPS-induced IL-6, IL-12p40 and IL-12p70 responses and increased IL-10. Reduction in IL-6 and IL-12p40 was also seen in human MDMs. Further, we observe cellular changes that resemble necrotic-like cell death in murine BMDMs. Induction of cell death required uptake of the peptide by phagocytosis, as it could be inhibited with cytochalasin D. Proteomic analysis showed upregulated M2 markers, antioxidant and metabolic proteins and downregulated interferon-inducible proteins. We have also developed a topical delivery system that penetrates both human and murine skin explants and offers superior protection from imiquimod-induced psoriasis applied daily, compared to a single injected dose. Topical RP23 also offers moderate protection from disease in the oxazolone-induced AD model. Use in either model did not affect spleen/ILN weights, suggesting localised suppression of inflammation. Topical RP23 treatment of inflamed and non-inflamed skin showed uptake by CD64+ macrophages and DCs and reduced proportions of total DCs. We also observed reduced IL-6, IL-12p40 and IL-17A/F production, neutrophil and Rorγt+ γδ T cell proportions in psoriatic murine skin and reduced CD11b+ cells in skin-draining lymph nodes. To conclude, we have demonstrated RP23 has significant therapeutic potential as a topical therapy for psoriasis and AD and identified molecular and cellular mechanisms that warrant further investigation