MTH1 Inhibitors for the Treatment of Psoriasis
| Autor: | Deepti Verma, Therese Pham, Martin Scobie, Thomas Helleday, Ulrika Warpman Berglund, Florence Sjögren, Charlotta Enerbäck, Claudia Bamberg, Ines Köhler, Stella Karsten, Cecilia Bivik Eding |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Keratinocytes Biopsy Cell- och molekylärbiologi Primary Cell Culture Apoptosis Dermatology medicine.disease_cause Administration Cutaneous Biochemistry Peripheral blood mononuclear cell 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Downregulation and upregulation Psoriasis Cell Line Tumor medicine Animals Humans Molecular Biology Skin Imiquimod 7-Aminoactinomycin D Chemistry Cell Biology medicine.disease Phosphoric Monoester Hydrolases Disease Models Animal Oxidative Stress 030104 developmental biology medicine.anatomical_structure DNA Repair Enzymes 030220 oncology & carcinogenesis Cancer research Female Lymph Keratinocyte Oxidative stress Cell and Molecular Biology |
| ISSN: | 0022-202X |
| Popis: | Inflammatory diseases, including psoriasis, are characterized by changes in redox regulation. The MTH1 prevents the incorporation of oxidized nucleotides during DNA replication. Using MTH1 small-molecule inhibitors, we found induced apoptosis through 8-oxodeoxyguanosine triphosphate accumulation and DNA double-strand breaks after oxidative stress in normal and malignant keratinocytes. In psoriasis, we detected increased MTH1 expression in lesional skin and PBMCs compared with that in the controls. Using the imiquimod psoriasis mouse model, we found that MTH1 inhibition diminished psoriatic histological characteristics and normalized the levels of neutrophils and T cells in the skin and skin-draining lymph nodes. The inhibition abolished the expression of T helper type 17-associated cytokines in the skin, which was in line with decreased levels of IL-17-producing gd 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. Funding Agencies|Ingrid Asp Psoriasis Foundation; Welander Foundation; Swedish Psoriasis Association; Swedish Cancer SocietySwedish Cancer Society [CAN-18-0658]; Svenska Smartafonden; Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [RB130224] |
| Databáze: | OpenAIRE |
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