MTH1 inhibitors for the treatment of psoriasis.

Abstract Inflammatory diseases, including psoriasis, are characterized by changes in redox regulation. The MutT homolog 1 (MTH1) prevents the incorporation of oxidized nucleotides during DNA replication. Using MTH1 small-molecule inhibitors, we found induced apoptosis through 8-oxo-dGTP accumulation and DNA double-strand breaks following oxidative stress in normal and malignant keratinocytes. In psoriasis, we detected increased MTH1 expression in lesional skin and PBMCs compared with controls. Using the Imiquimod (IMQ) psoriasis mouse model, we found that MTH1 inhibition diminished psoriatic histological characteristics and normalized the levels of neutrophils and T cells in skin and skin-draining lymph nodes. The inhibition abolished the expression of Th17-associated cytokines in the skin, which was in line with decreased levels of IL-17-producing γδ T cells in lymph nodes. In human keratinocytes, MTH1 inhibition prevented the upregulation of IL-17 downstream genes, which was independent of ROS-induced apoptosis. In conclusion, our data support MTH1 inhibition using small molecules suitable for topical application, as a promising therapeutic approach to psoriasis.