{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:58:14Z","timestamp":1780635494791,"version":"3.54.1"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T00:00:00Z","timestamp":1729555200000},"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:sec><jats:title>Background<\/jats:title><jats:p>Host-related factors highly regulate the increased circulation of neutrophils during <jats:italic>Leishmania<\/jats:italic> infection. Platelet-derived Dickkopf-1 (DKK1) is established as a high-affinity ligand to LRP6. Recently, we demonstrated that DKK1 upregulates leukocyte-platelet aggregation, infiltration of neutrophils to the draining lymph node and Th2 differentiation during <jats:italic>Leishmania<\/jats:italic> infection, suggesting the potential involvement of the DKK1-LRP6 signalling pathway in neutrophil migration in infectious diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we further explored the potential role of DKK1-LRP6 signalling in the migration and longevity of activated neutrophils in the infection site using BALB\/c mice with PMNs deficient in LRP6 (LRP6<jats:sup>NKO<\/jats:sup>) or BALB\/c mice deficient in both PMN LRP6 and platelet DKK1 (LRP6<jats:sup>NKO<\/jats:sup> DKK1<jats:sup>PKO<\/jats:sup>). Relative to the infected wild-type BALB\/c mice, reduced neutrophil activation at the infection site of LRP6<jats:sup>NKO<\/jats:sup> or LRP6<jats:sup>NKO<\/jats:sup> DKK1<jats:sup>PKO<\/jats:sup> mice was noted. The neutrophils obtained from either infected LRP6<jats:sup>NKO<\/jats:sup> or LRP6<jats:sup>NKO<\/jats:sup> DKK1<jats:sup>PKO<\/jats:sup> mice additionally showed a high level of apoptosis. Notably, the level of LRP6 expressing neutrophils was elevated in infected BALB\/c mice. Relative to infected BALB\/c mice, a significant reduction in parasite load was observed in both LRP6<jats:sup>NKO<\/jats:sup> and LRP6<jats:sup>NKO<\/jats:sup> DKK1<jats:sup>PKO<\/jats:sup> infected mice. Notably, DKK1 levels were comparable in the LRP6<jats:sup>NKO<\/jats:sup> and BALB\/c mice in response to infection, indicating that PMN activation is the major pathway for DKK1 in promoting parasitemia. Parasite-specific components also play a crucial role in modulating neutrophil circulation in <jats:italic>Leishmania<\/jats:italic> disease. Thus, we further determine the contribution of <jats:italic>Leishmania<\/jats:italic> membrane components in the migration of neutrophils to the infection site using null mutants deficient in LPG synthesis (<jats:italic>\u0394lpg1<jats:sup>-<\/jats:sup><\/jats:italic>) or lacking all ether phospholipids (plasmalogens, LPG, and GIPLs) synthesis (<jats:italic>\u0394ads1<jats:sup>-<\/jats:sup><\/jats:italic>). Relative to the WT controls, <jats:italic>\u0394ads1<jats:sup>-<\/jats:sup><\/jats:italic> parasite-infected mice showed a sustained decrease in neutrophils and neutrophil-platelet aggregates (for at least 14 days PI), while neutrophils returned to normal in <jats:italic>\u0394lpg1<jats:sup>-<\/jats:sup><\/jats:italic> parasite-infected mice after day 3 PI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results suggest that DKK1 signalling and <jats:italic>Leishmania<\/jats:italic> pathogen-associated molecular patterns appear to regulate the migration and sustenance of viable activated neutrophils in the infection site resulting in chronic type 2 cell-mediated inflammation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1473133","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T05:00:45Z","timestamp":1729573245000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Leishmania major surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site"],"prefix":"10.3389","volume":"15","author":[{"given":"Olivia C.","family":"Ihedioha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley Q.","family":"Marcarian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anutr","family":"Sivakoses","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Beverley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"McMahon-Pratt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred L. 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