MTH1 Inhibitors for the Treatment of Psoriasis

被引：15

作者：

Eding, Cecilia Bivik ^{[1
]}

Kohler, Ines ^{[1
]}

Verma, Deepti ^{[1
]}

Sjogren, Florence ^{[1
]}

Bamberg, Claudia ^{[2
]}

Karsten, Stella ^{[3
]}

Pham, Therese ^{[3
]}

Scobie, Martin ^{[3
]}

Helleday, Thomas ^{[3
,4
]}

Berglund, Ulrika Warpman ^{[3
]}

Enerback, Charlotta ^{[1
]}

机构：

[1] Linkoping Univ, Ingrid Asp Psoriasis Res Ctr, Dept Biomed & Clin Sci, Div Dermatol, Linkoping, Sweden

[2] Vastervik Hosp, Dept Dermatol, Vastervik, Sweden

[3] Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Stockholm, Sweden

[4] Univ Sheffield, Dept Oncol & Metab, Weston Pk Canc Ctr, Sheffield, S Yorkshire, England

来源：

JOURNAL OF INVESTIGATIVE DERMATOLOGY | 2021年 / 141卷 / 08期

关键词：

DELTA T-CELLS; OXIDATIVE STRESS; EXPRESSION; MICE;

D O I：

10.1016/j.jid.2021.01.026

中图分类号：

R75 [皮肤病学与性病学];

学科分类号：

100206 ;

摘要：

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.

引用

页码：2037 / +

页数：16

共 28 条

[1] Oxidative stress and psoriasis: the effect of antitumour necrosis factor- inhibitor treatment [J].

Bacchetti, T. ;

Campanati, A. ;

Ferretti, G. ;

Simonetti, O. ;

Liberati, G. ;

Offidani, A. M. .

BRITISH JOURNAL OF DERMATOLOGY, 2013, 168 (05) :984-989

[2] Validation and development of MTH1 inhibitors for treatment of cancer [J].

Berglund, U. Warpman ;

Sanjiv, K. ;

Gad, H. ;

Kalderen, C. ;

Koolmeister, T. ;

Pham, T. ;

Gokturk, C. ;

Jafari, R. ;

Maddalo, G. ;

Seashore-Ludlow, B. ;

Chernobrovkin, A. ;

Manoilov, A. ;

Pateras, I. S. ;

Rasti, A. ;

Jemth, A. -S. ;

Almlof, I. ;

Loseva, O. ;

Visnes, T. ;

Einarsdottir, B. O. ;

Gaugaz, F. Z. ;

Saleh, A. ;

Platzack, B. ;

Wallner, O. A. ;

Vallin, K. S. A. ;

Henriksson, M. ;

Wakchaure, P. ;

Borhade, S. ;

Herr, P. ;

Kallberg, Y. ;

Baranczewski, P. ;

Homan, E. J. ;

Wiita, E. ;

Nagpal, V. ;

Meijer, T. ;

Schipper, N. ;

Rudd, S. G. ;

Brautigam, L. ;

Lindqvist, A. ;

Filppula, A. ;

Lee, T-C. ;

Artursson, P. ;

Nilsson, J. A. ;

Gorgoulis, V. G. ;

Lehtio, J. ;

Zubarev, R. A. ;

Scobie, M. ;

Helleday, T. .

ANNALS OF ONCOLOGY, 2016, 27 (12) :2275-2283

[3]

Cai YH, 2011, IMMUNITY, V35, P596, DOI 10.1016/j.immuni.2011.08.001

[4] Oxidative stress involvement in psoriasis: a systematic review [J].

Cannavo, Serafinella Patrizia ;

Riso, Gabriella ;

Casciaro, Marco ;

Di Salvo, Eleonora ;

Gangemi, Sebastiano .

FREE RADICAL RESEARCH, 2019, 53 (08) :829-840

[5] DNA damage and innate immunity: links and trade-offs [J].

Chatzinikolaou, Georgia ;

Karakasilioti, Ismene ;

Garinis, George A. .

TRENDS IN IMMUNOLOGY, 2014, 35 (09) :429-435

[6] Impact of methotrexate on oxidative stress and apoptosis markers in psoriatic patients [J].

Elango, Tamilselvi ;

Dayalan, Haripriya ;

Gnanaraj, Pushpa ;

Malligarjunan, Hemamalini ;

Subramanian, Swapna .

CLINICAL AND EXPERIMENTAL MEDICINE, 2014, 14 (04) :431-437

[7] Association of MTH1 expression with the tumor malignant potential and poor prognosis in patients with resected lung cancer [J].

Fujishita, Takatoshi ;

Okamoto, Tatsuro ;

Akamine, Takaki ;

Takamori, Shinkichi ;

Takada, Kazuki ;

Katsura, Masakazu ;

Toyokawa, Goji ;

Shoji, Fumihiro ;

Shimokawa, Mototsugu ;

Oda, Yoshinao ;

Nakabeppu, Yusaku ;

Maehara, Yoshihiko .

LUNG CANCER, 2017, 109 :52-57

[8] MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool [J].

Gad, Helge ;

Koolmeister, Tobias ;

Jemth, Ann-Sofie ;

Eshtad, Saeed ;

Jacques, Sylvain A. ;

Strom, Cecilia E. ;

Svensson, Linda M. ;

Schultz, Niklas ;

Lundback, Thomas ;

Einarsdottir, Berglind Osk ;

Saleh, Aljona ;

Gokturk, Camilla ;

Baranczewski, Pawel ;

Svensson, Richard ;

Berntsson, Ronnie P. -A. ;

Gustafsson, Robert ;

Stromberg, Kia ;

Sanjiv, Kumar ;

Jacques-Cordonnier, Marie-Caroline ;

Desroses, Matthieu ;

Gustavsson, Anna-Lena ;

Olofsson, Roger ;

Johansson, Fredrik ;

Homan, Evert J. ;

Loseva, Olga ;

Brautigam, Lars ;

Johansson, Lars ;

Hoglund, Andreas ;

Hagenkort, Anna ;

Pham, Therese ;

Altun, Mikael ;

Gaugaz, Fabienne Z. ;

Vikingsson, Svante ;

Evers, Bastiaan ;

Henriksson, Martin ;

Vallin, Karl S. A. ;

Wallner, Olov A. ;

Hammarstrom, Lars G. J. ;

Wiita, Elisee ;

Almlof, Ingrid ;

Kalderen, Christina ;

Axelsson, Hanna ;

Djureinovic, Tatjana ;

Puigvert, Jordi Carreras ;

Haggblad, Maria ;

Jeppsson, Fredrik ;

Martens, Ulf ;

Lundin, Cecilia ;

Lundgren, Bo ;

Granelli, Ingrid .

NATURE, 2014, 508 (7495) :215-+

[9] Neutrophils and redox stress in the pathogenesis of autoimmune disease [J].

Glennon-Alty, Laurence ;

Hackett, Angela P. ;

Chapman, Elinor A. ;

Wright, Helen L. .

FREE RADICAL BIOLOGY AND MEDICINE, 2018, 125 :25-35

[10] Deficiency in IL-17-committed Vγ4+ γδ T cells in a spontaneous Sox13-mutant CD45.1+ congenic mouse substrain provides protection from dermatitis [J].

Gray, Elizabeth E. ;

Ramirez-Valle, Francisco ;

Xu, Ying ;

Wu, Shuang ;

Wu, Zhihao ;

Karjalainen, Klaus E. ;

Cyster, Jason G. .

NATURE IMMUNOLOGY, 2013, 14 (06) :584-+

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