{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:16:04Z","timestamp":1789168564295,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009649","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T00:00:00Z","timestamp":1623715200000}}],"reference-count":80,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T00:00:00Z","timestamp":1622678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K15140"],"award-info":[{"award-number":["18K15140"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K06996"],"award-info":[{"award-number":["21K06996"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kitasato University Integrative Research Program of the Graduate School of Medical Sciences"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Parasitic helminths can reside in humans owing to their ability to disrupt host protective immunity. Receptor for advanced glycation end products (RAGE), which is highly expressed in host skin, mediates inflammatory responses by regulating the expression of pro-inflammatory cytokines and endothelial adhesion molecules. In this study, we evaluated the effects of venestatin, an EF-hand Ca<jats:sup>2+<\/jats:sup>-binding protein secreted by the parasitic helminth <jats:italic>Strongyloides venezuelensis<\/jats:italic>, on RAGE activity and immune responses. Our results demonstrated that venestatin bound to RAGE and downregulated the host immune response. Recombinant venestatin predominantly bound to the RAGE C1 domain in a Ca<jats:sup>2+<\/jats:sup>-dependent manner. Recombinant venestatin effectively alleviated RAGE-mediated inflammation, including footpad edema in mice, and pneumonia induced by an exogenous RAGE ligand. Infection experiments using <jats:italic>S<\/jats:italic>. <jats:italic>venezuelensis<\/jats:italic> larvae and venestatin silencing via RNA interference revealed that endogenous venestatin promoted larval migration from the skin to the lungs in a RAGE-dependent manner. Moreover, endogenous venestatin suppressed macrophage and neutrophil accumulation around larvae. Although the invasion of larvae upregulated the abundance of RAGE ligands in host skin tissues, mRNA expression levels of tumor necrosis factor-\u03b1, cyclooxygenase-2, endothelial adhesion molecules vascular cell adhesion protein-1, intracellular adhesion molecule-1, and E-selectin were suppressed by endogenous venestatin. Taken together, our results indicate that venestatin suppressed RAGE-mediated immune responses in host skin induced by helminthic infection, thereby promoting larval migration. The anti-inflammatory mechanism of venestatin may be targeted for the development of anthelminthics and immunosuppressive agents for the treatment of RAGE-mediated inflammatory diseases.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009649","type":"journal-article","created":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T18:17:04Z","timestamp":1622744224000},"page":"e1009649","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Venestatin from parasitic helminths interferes with receptor for advanced glycation end products (RAGE)-mediated immune responses to promote larval migration"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4344-5128","authenticated-orcid":true,"given":"Daigo","family":"Tsubokawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2759-9167","authenticated-orcid":true,"given":"Taisei","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Man","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4885-7970","authenticated-orcid":true,"given":"Takahiro","family":"Kusakabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1326-4649","authenticated-orcid":true,"given":"Yasuhiko","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,3]]},"reference":[{"issue":"4","key":"ppat.1009649.ref001","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1172\/JCI34261","article-title":"Helminth infections: the great neglected tropical diseases","volume":"118","author":"PJ Hotez","year":"2008","journal-title":"J Clin Invest"},{"issue":"6","key":"ppat.1009649.ref002","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/nri2992","article-title":"Diversity and dialogue in immunity to helminths","volume":"11","author":"JE Allen","year":"2011","journal-title":"Nat Rev Immunol"},{"issue":"6093","key":"ppat.1009649.ref003","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1126\/science.1221064","article-title":"New paradigms in type 2 immunity","volume":"337","author":"B Pulendran","year":"2012","journal-title":"Science"},{"issue":"10","key":"ppat.1009649.ref004","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.pt.2016.05.004","article-title":"Eosinophils in Helminth Infection: Defenders and Dupes","volume":"32","author":"L Huang","year":"2016","journal-title":"Trends Parasitol"},{"issue":"4","key":"ppat.1009649.ref005","doi-asserted-by":"crossref","first-page":"e1003250","DOI":"10.1371\/journal.ppat.1003250","article-title":"Immune regulation during helminth infections","volume":"9","author":"NM Girgis","year":"2013","journal-title":"PLoS Pathog"},{"issue":"2","key":"ppat.1009649.ref006","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.molbiopara.2014.03.007","article-title":"Secretory products of helminth parasites as immunomodulators","volume":"195","author":"W. 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