{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T19:32:20Z","timestamp":1779910340459,"version":"3.53.1"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T00:00:00Z","timestamp":1708387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 \u03b3\u03b4T 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.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1344878","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T00:44:30Z","timestamp":1708389870000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Tick cysteine protease inhibitors suppress immune responses in mannan-induced psoriasis-like inflammation"],"prefix":"10.3389","volume":"15","author":[{"given":"Huimei","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Amine","family":"Jmel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwei","family":"Chai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maolin","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Hui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kutty Selva","family":"Nandakumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail","family":"Kotsyfakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81894","article-title":"Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases","volume":"126","author":"Dragin","year":"2016","journal-title":"J Clin Invest"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2012.02.001","article-title":"Updated assessment of the prevalence, spectrum and case definition of autoimmune disease","volume":"11","author":"Hayter","year":"2012","journal-title":"Autoimmun Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds344","article-title":"Conditional analysis identifies three novel major histocompatibility complex loci associated with psoriasis","volume":"21","author":"Knight","year":"2012","journal-title":"Hum Mol Genet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.4006","article-title":"Pathophysiology, clinical presentation, and treatment of psoriasis: A review","volume":"323","author":"Armstrong","year":"2020","journal-title":"JAMA"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32549-6","article-title":"Psoriasis","volume":"397","author":"Griffiths","year":"2021","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2014.05.014","article-title":"Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity","volume":"26","author":"Schafer","year":"2014","journal-title":"Cell Signalling"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1177\/1203475416676030","article-title":"Real-world experience with apremilast in treating psoriasis","volume":"21","author":"Mayba","year":"2017","journal-title":"J Cutan Med Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1806382","article-title":"Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis","volume":"379","author":"Papp","year":"2018","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.jprot.2015.07.005","article-title":"Modulation of host immunity by tick saliva","volume":"128","author":"Kotal","year":"2015","journal-title":"J Proteomics"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2741\/3363","article-title":"The role of saliva in tick feeding","volume":"14","author":"Francischetti","year":"2009","journal-title":"Front Biosci (Landmark Ed)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22020892","article-title":"Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite-Host Crosstalk","volume":"22","author":"Jmel","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.205.18.2843","article-title":"Exploring the sialome of the tick Ixodes scapularis","volume":"205","author":"Valenzuela","year":"2002","journal-title":"J Exp Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.919786","article-title":"Transcriptomic analysis of the tick midgut and salivary gland responses upon repeated blood-feeding on a vertebrate host","volume":"12","author":"Medina","year":"2022","journal-title":"Front Cell Infection Microbiol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021556","article-title":"Tick salivary kunitz-type inhibitors: targeting host hemostasis and immunity to mediate successful blood feeding","volume":"24","author":"Jmel","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900075","article-title":"The immunomodulatory action of sialostatin L on dendritic cells reveals its potential to interfere with autoimmunity","volume":"182","author":"Sa-Nunes","year":"2009","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703143200","article-title":"Selective cysteine protease inhibition contributes to blood-feeding success of the tick Ixodes scapularis","volume":"282","author":"Kotsyfakis","year":"2007","journal-title":"J Biol Chem"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01679-14","article-title":"The tick salivary protein sialostatin L2 inhibits caspase-1-mediated inflammation during Anaplasma phagocytophilum infection","volume":"82","author":"Chen","year":"2014","journal-title":"Infect Immun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03034-3","article-title":"The structure and function of Iristatin, a novel immunosuppressive tick salivary cystatin","volume":"76","author":"Kotal","year":"2019","journal-title":"Cell Mol Life Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22105371","article-title":"Mialostatin, a novel midgut cystatin from ixodes ricinus ticks: crystal structure and regulation of host blood digestion","volume":"22","author":"Kotal","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2010.07220.x","article-title":"The crystal structures of two salivary cystatins from the tick Ixodes scapularis and the effect of these inhibitors on the establishment of Borrelia burgdorferi infection in a murine model","volume":"77","author":"Kotsyfakis","year":"2010","journal-title":"Mol Microbiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.626200","article-title":"Iripin-3, a new salivary protein isolated from ixodes ricinus ticks, displays immunomodulatory and anti-hemostatic properties in vitro","volume":"12","author":"Chlastakova","year":"2021","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)69848-0","article-title":"Phase separation of integral membrane proteins in Triton X-114 solution","volume":"256","author":"Bordier","year":"1981","journal-title":"J Biol Chem"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401823","article-title":"Tick salivary sialostatin L represses the initiation of immune responses by targeting IRF4-dependent transcription in murine mast cells","volume":"195","author":"Klein","year":"2015","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.818173","article-title":"Estrogen acts through estrogen receptor-beta to promote mannan-induced psoriasis-like skin inflammation","volume":"13","author":"Wu","year":"2022","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1093\/cei\/uxad004","article-title":"Comparative studies on mannan and imiquimod induced experimental plaque psoriasis inflammation in inbred mice","volume":"211","author":"Wu","year":"2023","journal-title":"Clin Exp Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e4845","DOI":"10.21769\/BioProtoc.4845","article-title":"Epicutaneous application of mannan induces psoriasis-like inflammation in an inbred mouse strain","volume":"13","author":"Wu","year":"2023","journal-title":"Bio Protoc"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1992.tb07805.x","article-title":"Is epidermal-cell proliferation in psoriatic skin-grafts on nude-mice driven by T-cell derived cytokines","volume":"126","author":"Baker","year":"1992","journal-title":"Br J Dermatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100529","article-title":"The tick salivary protein sialostatin L inhibits the th9-derived production of the asthma-promoting cytokine IL-9 and is effective in the prevention of experimental asthma","volume":"188","author":"Horka","year":"2012","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12162","article-title":"Tick salivary cystatin sialostatin L2 suppresses IFN responses in mouse dendritic cells","volume":"37","author":"Lieskovska","year":"2015","journal-title":"Parasite Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01526-15","article-title":"The tick protein sialostatin L2 binds to annexin A2 and inhibits NLRC4-mediated inflammasome activation","volume":"84","author":"Wang","year":"2016","journal-title":"Infect Immun"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513010200","article-title":"Antiinflammatory and immunosuppressive activity of sialostatin L, a salivary cystatin from the tick Ixodes scapularis","volume":"281","author":"Kotsyfakis","year":"2006","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21706","article-title":"Transforming growth factor-beta 1 (TGF-beta 1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis","volume":"219","author":"Ferrari","year":"2009","journal-title":"J Cell Physiol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.941071","article-title":"Dendritic cells and macrophages in the pathogenesis of psoriasis","volume":"13","author":"Kamata","year":"2022","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27179","article-title":"Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation","volume":"116","author":"Stratis","year":"2006","journal-title":"J Clin Invest"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1405798111","article-title":"Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice","volume":"111","author":"Khmaladze","year":"2014","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B36","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.immuni.2011.08.001","article-title":"Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation","volume":"35","author":"Cai","year":"2011","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1007\/s12026-020-09149-1","article-title":"The role of Th17 cells in psoriasis","volume":"68","author":"Li","year":"2020","journal-title":"Immunol Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nature05663","article-title":"Pathogenesis and therapy of psoriasis","volume":"445","author":"Lowes","year":"2007","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03704-z","article-title":"Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation","volume":"9","author":"Li","year":"2018","journal-title":"Nat Commun"},{"key":"B40","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1172\/JCI33263","article-title":"IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation","volume":"118","author":"Ma","year":"2008","journal-title":"J Clin Invest"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61862","article-title":"Rorgammat+ innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice","volume":"122","author":"Pantelyushin","year":"2012","journal-title":"J Clin Invest"},{"key":"B42","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.jaci.2020.12.628","article-title":"IL-25 (IL-17E) in epithelial immunology and pathophysiology","volume":"148","author":"Borowczyk","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.2478\/v10039-010-0037-0","article-title":"IL-8, IL-12 and IL-10 cytokines generation by neutrophils, fibroblasts and neutrophils- fibroblasts interaction in psoriasis","volume":"55","author":"Glowacka","year":"2010","journal-title":"Adv Med Sci"},{"key":"B44","article-title":"IL-10 implications in psoriasis","volume":"2","author":"Al-Robaee","year":"2008","journal-title":"Int J Health Sci (Qassim)"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.2001.01248.x","article-title":"Response of psoriasis to interleukin-10 is associated with suppression of cutaneous type 1 inflammation, downregulation of the epidermal interleukin-8\/CXCR2 pathway and normalization of keratinocyte maturation","volume":"116","author":"Reich","year":"2001","journal-title":"J Invest Dermatol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2017.1279054","article-title":"The role of IL-4 in psoriasis","volume":"13","author":"Hahn","year":"2017","journal-title":"Expert Rev Clin Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nm804","article-title":"Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease","volume":"9","author":"Ghoreschi","year":"2003","journal-title":"Nat Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11061397","article-title":"Roles of cysteine proteases in biology and pathogenesis of parasites","volume":"11","author":"Yang","year":"2023","journal-title":"Microorganisms"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2009.00990.x","article-title":"Upregulation of cathepsin S in psoriatic keratinocytes","volume":"19","author":"Schonefuss","year":"2010","journal-title":"Exp Dermatol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00812","article-title":"The use of tick salivary proteins as novel therapeutics","volume":"10","author":"Chmelar","year":"2019","journal-title":"Front Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2015.02.1127","article-title":"Genital psoriasis is associated with significant impairment in quality of life and sexual functioning","volume":"72","author":"Ryan","year":"2015","journal-title":"J Am Acad Dermatol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2017.05.019","article-title":"Psoriasis and suicidality: A systematic review and meta-analysis","volume":"77","author":"Singh","year":"2017","journal-title":"J Am Acad Dermatol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1007\/s00403-022-02377-5","article-title":"Risk for incident suicidality among psoriasis patients: a systematic review and meta-analysis","volume":"315","author":"Hung","year":"2022","journal-title":"Arch Dermatol Res"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222312793","article-title":"The cytokine mediated molecular pathophysiology of psoriasis and its clinical implications","volume":"22","author":"Singh","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212127","article-title":"Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation","volume":"77","author":"Glatt","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01682","article-title":"The IL-17 family of cytokines in psoriasis: IL-17A and beyond","volume":"9","author":"Brembilla","year":"2018","journal-title":"Front Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200901","article-title":"Cathepsin K is involved in development of psoriasis-like skin lesions through TLR-dependent Th17 activation","volume":"190","author":"Hirai","year":"2013","journal-title":"J Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620954114","article-title":"Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36gamma","volume":"114","author":"Ainscough","year":"2017","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-018-8668-1","article-title":"Psoriasis: from pathogenesis to targeted therapies","volume":"54","author":"Conrad","year":"2018","journal-title":"Clin Rev Allergy Immunol"}],"updated-by":[{"DOI":"10.3389\/fimmu.2025.1699570","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1344878\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T14:30:42Z","timestamp":1757687442000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1344878\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,20]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2024.1344878"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1344878","relation":{"correction":[{"id-type":"doi","id":"10.3389\/fimmu.2025.1699570","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,20]]},"article-number":"1344878"}}