{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:15:33Z","timestamp":1785417333328,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,31]]},"group-title":"Immunology","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["AI-137060"],"award-info":[{"award-number":["AI-137060"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Dickkopf-1(DKK1) is a classical Wnt antagonist, which is released at the initiation of\n                  <jats:italic>Leishmania major<\/jats:italic>\n                  infection through platelet TLR1\/2 activation. Using BALB\/c mice deficient in platelet MyD88 (MyD88\n                  <jats:sup>PKO<\/jats:sup>\n                  ) or platelet DKK1 (DKK1\n                  <jats:sup>PKO<\/jats:sup>\n                  ), we assessed whether the transmission of activation signals through MyD88 and subsequent release of DKK1 are critical in regulating the immune response to\n                  <jats:italic>L. major<\/jats:italic>\n                  . At the site of infection, the levels of neutrophil platelet aggregates and activated neutrophils of MyD88\n                  <jats:sup>(PKO)<\/jats:sup>\n                  and DKK1\n                  <jats:sup>(PKO)<\/jats:sup>\n                  mice were reduced. Further, these mice mounted anti-leishmanial Th1-responses and failed to develop progressive lesions. In contrast, WT BALB\/c-infected mice developed progressive disease associated with elevated IL-10-producing Th1 and Th2 T cells. Further, elevated CD206\n                  <jats:sup>+<\/jats:sup>\n                  M2 macrophages and tolerogenic DC-10 cells, which favor parasite proliferation, were observed. In vitro, DKK1 promoted DC IL-10 production and blocked TNF\u03b1-induction of IL-12. Overall, these results indicate that platelet-DKK1 promotes disease progression through the induction of tolerogenic DCs and subsequent pathological Th2 and IL-10-Th1 T cell-responses.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary statement<\/jats:title>\n                  <jats:p>\n                    Platelet DKK1 produced in response to TLR1\/2 signaling by\n                    <jats:italic>Leishmania<\/jats:italic>\n                    parasites drives development of non-healing responses. In vivo\/ in vitro analyses indicate that the mechanism underlying this process is the promotion of tolerogenic dendritic cells, driving Th2 and Th1-IL-10 T cell responses.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"656395v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.27.656395","type":"posted-content","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T01:30:11Z","timestamp":1748741411000},"source":"Crossref","is-referenced-by-count":1,"title":["Platelet DKK1 promotes tolerogenic dendritic cells and non-healing responses in cutaneous leishmaniasis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9079-0787","authenticated-orcid":false,"given":"Olivia C.","family":"Ihedioha","sequence":"first","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4321-4645","authenticated-orcid":false,"given":"Anutr","family":"Sivakoses","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley Q.","family":"Marcarian","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malini","family":"Sajeev","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0872-8779","authenticated-orcid":false,"given":"Diane","family":"McMahon-Pratt","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Infectious Diseases, Yale School of Public Health, New Haven, CT, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred L.M.","family":"Bothwell","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America"},{"name":"Department of Immunobiology, Yale University, New Haven, Connecticut, United 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