Protease inhibitors regulate various biological processes and prevent host tissue/organ damage. Specific inhibition/regulation of proteases is clinically valuable for treating several diseases. Psoriasis affects the skin in the limbs and scalp of the body, and the contribution of cysteine and serine proteases to the development of skin inflammation is well documented. Cysteine protease inhibitors from ticks have high specificity, selectivity, and affinity to their target proteases and are efficient immunomodulators. However, their potential therapeutic effect on psoriasis pathogenesis remains to be determined. Therefore, we tested four tick cystatins (Sialostatin L, Sialostatin L2, Iristatin, and Mialostatin) in the recently developed, innate immunity-dependent mannan-induced psoriasis model. We explored the effects of protease inhibitors on clinical symptoms and histological features. In addition, the number and percentage of immune cells (dendritic cells, neutrophils, macrophages, and γδT cells) by flow cytometry, immunofluorescence/immunohistochemistry and, the expression of pro-inflammatory cytokines (TNF-a, IL-6, IL-22, IL-23, and IL-17 family) by qPCR were analyzed using skin, spleen, and lymph node samples. Tick protease inhibitors have significantly decreased psoriasis symptoms and disease manifestations but had differential effects on inflammatory responses and immune cell populations, suggesting different modes of action of these inhibitors on psoriasis-like inflammation. Thus, our study demonstrates, for the first time, the usefulness of tick-derived protease inhibitors for treating skin inflammation in patients.

Department of Endocrinology 5th Affiliated Hospital Southern Medical University Guangzhou China

Department of Environmental and Biosciences School of Business Innovation and Sustainability Halmstad University Halmstad Sweden

Department of Pharmacy The Eighth Affiliated City Hospital of Guangzhou Medical University The Eighth People's Hospital of Guangzhou Guangzhou China

Department of Pulmonary and Critical Care Medicine Zhujiang Hospital Southern Medical University Guangzhou China

Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical Sciences Southern Medical University Guangzhou China

Institute of Molecular Biology and Biotechnology Foundation for Research and Technology Hellas Heraklion Crete Greece

Institute of Parasitology Biology Centre Czech Academy of Sciences České Budějovice Czechia

Karolinska Institute United Medical Inflammation Center School of Pharmaceutical Sciences Southern Medical University Guangzhou China

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