{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T04:08:35Z","timestamp":1774584515730,"version":"3.50.1"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2015,12,10]],"date-time":"2015-12-10T00:00:00Z","timestamp":1449705600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,12,10]],"date-time":"2015-12-10T00:00:00Z","timestamp":1449705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neutrophils are the predominant recruited and infected cells during the early stages of <jats:italic>Leishmania major<\/jats:italic> infection in the skin, and depletion of neutrophils promotes immunity to infection transmitted by sand fly bite. In order to better understand how the acute neutrophilic response suppresses immunity, we assessed the consequences of the interaction between neutrophils recovered from the skin-inoculation site and bone marrow-derived dendritic cells (DCs) <jats:italic>in vitro<\/jats:italic>. The capture of infected, apoptotic neutrophils by the DCs completely inhibited their cross-presentation function that was dependent on engagement of the receptor tyrosine kinase Mer on the DCs. The capture of uninfected neutrophils, or neutrophils infected with <jats:italic>Toxoplasma gondii<\/jats:italic>, had only slight immunomodulatory effects. These studies define the clearance of infected, apoptotic neutrophils by DCs and Mer receptor signaling as central to the early immune evasion strategies of <jats:italic>L. major<\/jats:italic>, with relevance to other vector-borne pathogens delivered by bite to the skin.<\/jats:p>","DOI":"10.1038\/cddis.2015.351","type":"journal-article","created":{"date-parts":[[2015,12,10]],"date-time":"2015-12-10T13:44:13Z","timestamp":1449755053000},"page":"e2018-e2018","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Apoptotic cell clearance of Leishmania major-infected neutrophils by dendritic cells inhibits CD8+ T-cell priming in vitro by Mer tyrosine kinase-dependent signaling"],"prefix":"10.1038","volume":"6","author":[{"given":"F L","family":"Ribeiro-Gomes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Romano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E","family":"Roff\u00ea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N C","family":"Peters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Debrabant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"Sacks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,12,10]]},"reference":[{"key":"BFcddis2015351_CR1","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1038\/cdd.2008.58","volume":"15","author":"RB Birge","year":"2008","unstructured":"Birge RB, Ucker DS . Innate apoptotic immunity: the calming touch of death. Cell Death Differ 2008; 15: 1096\u20131102.","journal-title":"Cell Death Differ"},{"key":"BFcddis2015351_CR2","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/BF00214700","volume":"193","author":"PG Clarke","year":"1996","unstructured":"Clarke PG, Clarke S . Nineteenth century research on naturally occurring cell death and related phenomena. Anat Embryol 1996; 193: 81\u201399.","journal-title":"Anat Embryol"},{"key":"BFcddis2015351_CR3","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1172\/JCI1112","volume":"101","author":"VA Fadok","year":"1998","unstructured":"Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM . Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine\/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 1998; 101: 890\u2013898.","journal-title":"J Clin Invest"},{"key":"BFcddis2015351_CR4","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.4049\/jimmunol.168.4.1627","volume":"168","author":"LM Stuart","year":"2002","unstructured":"Stuart LM, Lucas M, Simpson C, Lamb J, Savill J, Lacy-Hulbert A . Inhibitory effects of apoptotic cell ingestion upon endotoxin-driven myeloid dendritic cell maturation. J Immunol 2002; 168: 1627\u20131635.","journal-title":"J Immunol"},{"key":"BFcddis2015351_CR5","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/37022","volume":"390","author":"RE Voll","year":"1997","unstructured":"Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I . Immunosuppressive effects of apoptotic cells. Nature 1997; 390: 350\u2013351.","journal-title":"Nature"},{"key":"BFcddis2015351_CR6","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1084\/jem.191.3.411","volume":"191","author":"RM Steinman","year":"2000","unstructured":"Steinman RM, Turley S, Mellman I, Inaba K . The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 2000; 191: 411\u2013416.","journal-title":"J Exp Med"},{"key":"BFcddis2015351_CR7","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/35003208","volume":"403","author":"CG Freire-de-Lima","year":"2000","unstructured":"Freire-de-Lima CG, Nascimento DO, Soares MB, Bozza PT, Castro-Faria-Neto HC, de Mello FG et al. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 2000; 403: 199\u2013203.","journal-title":"Nature"},{"key":"BFcddis2015351_CR8","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1084\/jem.20082058","volume":"206","author":"AI Medeiros","year":"2009","unstructured":"Medeiros AI, Serezani CH, Lee SP, Peters-Golden M . Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2\/EP2 signaling. J Exp Med 2009; 206: 61\u201368.","journal-title":"J Exp Med"},{"key":"BFcddis2015351_CR9","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1002\/eji.200636771","volume":"37","author":"M Aleman","year":"2007","unstructured":"Aleman M, de la Barrera S, Schierloh P, Yokobori N, Baldini M, Musella R et al. Spontaneous or Mycobacterium tuberculosis-induced apoptotic neutrophils exert opposite effects on the dendritic cell-mediated immune response. Eur J Immunol 2007; 37: 1524\u20131537.","journal-title":"Eur J Immunol"},{"key":"BFcddis2015351_CR10","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1126\/science.1159194","volume":"321","author":"NC Peters","year":"2008","unstructured":"Peters NC, Egen JG, Secundino N, Debrabant A, Kimblin N, Kamhawi S et al. In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies. Science 2008; 321: 970\u2013974.","journal-title":"Science"},{"key":"BFcddis2015351_CR11","doi-asserted-by":"publisher","first-page":"e1002536","DOI":"10.1371\/journal.ppat.1002536","volume":"8","author":"FL Ribeiro-Gomes","year":"2012","unstructured":"Ribeiro-Gomes FL, Peters NC, Debrabant A, Sacks DL . Efficient capture of infected neutrophils by dendritic cells in the skin inhibits the early anti-leishmania response. PLoS Pathog 2012; 8: e1002536.","journal-title":"PLoS Pathog"},{"key":"BFcddis2015351_CR12","doi-asserted-by":"publisher","first-page":"2713","DOI":"10.1128\/IAI.01600-13","volume":"82","author":"FL Ribeiro-Gomes","year":"2014","unstructured":"Ribeiro-Gomes FL, Roma EH, Carneiro MB, Doria NA, Sacks DL, Peters NC . Site-dependent recruitment of inflammatory cells determines the effective dose of Leishmania major. Infect Immun 2014; 82: 2713\u20132727.","journal-title":"Infect Immun"},{"key":"BFcddis2015351_CR13","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1182\/blood.V96.2.719","volume":"96","author":"N Faust","year":"2000","unstructured":"Faust N, Varas F, Kelly LM, Heck S, Graf T . Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood 2000; 96: 719\u2013726.","journal-title":"Blood"},{"key":"BFcddis2015351_CR14","doi-asserted-by":"publisher","first-page":"902","DOI":"10.4049\/jimmunol.167.2.902","volume":"167","author":"LC Gavrilescu","year":"2001","unstructured":"Gavrilescu LC, Denkers EY . IFN-gamma overproduction and high level apoptosis are associated with high but not low virulence Toxoplasma gondii infection. J Immunol 2001; 167: 902\u2013909.","journal-title":"J Immunol"},{"key":"BFcddis2015351_CR15","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1182\/blood-2006-04-017368","volume":"109","author":"P Sen","year":"2007","unstructured":"Sen P, Wallet MA, Yi Z, Huang Y, Henderson M, Mathews CE et al. Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kappaB activation in dendritic cells. Blood 2007; 109: 653\u2013660.","journal-title":"Blood"},{"key":"BFcddis2015351_CR16","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1084\/jem.20062293","volume":"205","author":"MA Wallet","year":"2008","unstructured":"Wallet MA, Sen P, Flores RR, Wang Y, Yi Z, Huang Y et al. MerTK is required for apoptotic cell-induced T cell tolerance. J Exp Med 2008; 205: 219\u2013232.","journal-title":"J Exp Med"},{"key":"BFcddis2015351_CR17","doi-asserted-by":"publisher","first-page":"3483","DOI":"10.4049\/jimmunol.1101549","volume":"187","author":"SC Choi","year":"2011","unstructured":"Choi SC, Simhadri VR, Tian L, Gil-Krzewska A, Krzewski K, Borrego F et al. Cutting edge: mouse CD300f (CMRF-35-like molecule-1) recognizes outer membrane-exposed phosphatidylserine and can promote phagocytosis. J Immunol 2011; 187: 3483\u20133487.","journal-title":"J Immunol"},{"key":"BFcddis2015351_CR18","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1084\/jem.20091508","volume":"207","author":"H Xi","year":"2010","unstructured":"Xi H, Katschke KJ Jr, Helmy KY, Wark PA, Kljavin N, Clark H et al. Negative regulation of autoimmune demyelination by the inhibitory receptor CLM-1. J Exp Med 2010; 207: 7\u201316.","journal-title":"J Exp Med"},{"key":"BFcddis2015351_CR19","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1038\/nri2214","volume":"7","author":"KS Ravichandran","year":"2007","unstructured":"Ravichandran KS, Lorenz U . Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol 2007; 7: 964\u2013974.","journal-title":"Nat Rev Immunol"},{"key":"BFcddis2015351_CR20","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/ni871","volume":"4","author":"HA Anderson","year":"2003","unstructured":"Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E . Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol 2003; 4: 87\u201391.","journal-title":"Nat Immunol"},{"key":"BFcddis2015351_CR21","doi-asserted-by":"publisher","first-page":"23869","DOI":"10.1074\/jbc.C400159200","volume":"279","author":"L Kask","year":"2004","unstructured":"Kask L, Trouw LA, Dahlback B, Blom AM . The C4b-binding protein-protein S complex inhibits the phagocytosis of apoptotic cells. J Biol Chem 2004; 279: 23869\u201323873.","journal-title":"J Biol Chem"},{"key":"BFcddis2015351_CR22","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.it.2011.04.009","volume":"32","author":"DL Bratton","year":"2011","unstructured":"Bratton DL, Henson PM . Neutrophil clearance: when the party is over, clean-up begins. Trends Immunol 2011; 32: 350\u2013357.","journal-title":"Trends Immunol"},{"key":"BFcddis2015351_CR23","doi-asserted-by":"publisher","first-page":"e1000484","DOI":"10.1371\/journal.ppat.1000484","volume":"5","author":"NC Peters","year":"2009","unstructured":"Peters NC, Kimblin N, Secundino N, Kamhawi S, Lawyer P, Sacks DL . Vector transmission of leishmania abrogates vaccine-induced protective immunity. PLoS Pathog 2009; 5: e1000484.","journal-title":"PLoS Pathog"},{"key":"BFcddis2015351_CR24","doi-asserted-by":"publisher","first-page":"e1004929","DOI":"10.1371\/journal.ppat.1004929","volume":"11","author":"BP Hurrell","year":"2015","unstructured":"Hurrell BP, Schuster S, Grun E, Coutaz M, Williams RA, Held W et al. Rapid sequestration of Leishmania mexicana by neutrophils contributes to the development of chronic lesion. PLoS Pathog 2015; 11: e1004929.","journal-title":"PLoS Pathog"},{"key":"BFcddis2015351_CR25","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1002\/eji.201344242","volume":"44","author":"D Ashok","year":"2014","unstructured":"Ashok D, Schuster S, Ronet C, Rosa M, Mack V, Lavanchy C et al. Cross-presenting dendritic cells are required for control of Leishmania major infection. Eur J Immunol 2014; 44: 1422\u20131432.","journal-title":"Eur J Immunol"},{"key":"BFcddis2015351_CR26","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1023\/B:APPT.0000031448.64969.fa","volume":"9","author":"FR DeLeo","year":"2004","unstructured":"DeLeo FR . Modulation of phagocyte apoptosis by bacterial pathogens. Apoptosis 2004; 9: 399\u2013413.","journal-title":"Apoptosis"},{"key":"BFcddis2015351_CR27","doi-asserted-by":"publisher","first-page":"6358","DOI":"10.4049\/jimmunol.168.12.6358","volume":"168","author":"N Perskvist","year":"2002","unstructured":"Perskvist N, Long M, Stendahl O, Zheng L . Mycobacterium tuberculosis promotes apoptosis in human neutrophils by activating caspase-3 and altering expression of Bax\/Bcl-xL via an oxygen-dependent pathway. J Immunol 2002; 168: 6358\u20136365.","journal-title":"J Immunol"},{"key":"BFcddis2015351_CR28","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/32183","volume":"392","author":"ML Albert","year":"1998","unstructured":"Albert ML, Sauter B, Bhardwaj N . Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998; 392: 86\u201389.","journal-title":"Nature"},{"key":"BFcddis2015351_CR29","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1189\/jlb.0905526","volume":"79","author":"AM Megiovanni","year":"2006","unstructured":"Megiovanni AM, Sanchez F, Robledo-Sarmiento M, Morel C, Gluckman JC, Boudaly S . Polymorphonuclear neutrophils deliver activation signals and antigenic molecules to dendritic cells: a new link between leukocytes upstream of T lymphocytes. J Leukoc Biol 2006; 79: 977\u2013988.","journal-title":"J Leukoc Biol"},{"key":"BFcddis2015351_CR30","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1038\/nm906","volume":"9","author":"UE Schaible","year":"2003","unstructured":"Schaible UE, Winau F, Sieling PA, Fischer K, Collins HL, Hagens K et al. Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat Med 2003; 9: 1039\u20131046.","journal-title":"Nat Med"},{"key":"BFcddis2015351_CR31","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1084\/jem.191.4.613","volume":"191","author":"U Yrlid","year":"2000","unstructured":"Yrlid U, Wick MJ . Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells. J Exp Med 2000; 191: 613\u2013624.","journal-title":"J Exp Med"},{"key":"BFcddis2015351_CR32","doi-asserted-by":"publisher","first-page":"6319","DOI":"10.4049\/jimmunol.173.10.6319","volume":"173","author":"L Zheng","year":"2004","unstructured":"Zheng L, He M, Long M, Blomgran R, Stendahl O . Pathogen-induced apoptotic neutrophils express heat shock proteins and elicit activation of human macrophages. J Immunol 2004; 173: 6319\u20136326.","journal-title":"J Immunol"},{"key":"BFcddis2015351_CR33","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nri2545","volume":"9","author":"DR Green","year":"2009","unstructured":"Green DR, Ferguson T, Zitvogel L, Kroemer G . Immunogenic and tolerogenic cell death. Nat Rev Immunol 2009; 9: 353\u2013363.","journal-title":"Nat Rev Immunol"},{"key":"BFcddis2015351_CR34","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1111\/j.1749-6632.2010.05744.x","volume":"1209","author":"G Lemke","year":"2010","unstructured":"Lemke G, Burstyn-Cohen T . TAM receptors and the clearance of apoptotic cells. Ann NY Acad Sci 2010; 1209: 23\u201329.","journal-title":"Ann NY Acad Sci"},{"key":"BFcddis2015351_CR35","doi-asserted-by":"publisher","first-page":"5635","DOI":"10.4049\/jimmunol.178.9.5635","volume":"178","author":"HM Seitz","year":"2007","unstructured":"Seitz HM, Camenisch TD, Lemke G, Earp HS, Matsushima GK . Macrophages and dendritic cells use different Axl\/Mertk\/Tyro3 receptors in clearance of apoptotic cells. J Immunol 2007; 178: 5635\u20135642.","journal-title":"J Immunol"},{"key":"BFcddis2015351_CR36","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1038\/ni.2986","volume":"15","author":"A Zagorska","year":"2014","unstructured":"Zagorska A, Traves PG, Lew ED, Dransfield I, Lemke G . Diversification of TAM receptor tyrosine kinase function. Nat Immunol 2014; 15: 920\u2013928.","journal-title":"Nat Immunol"},{"key":"BFcddis2015351_CR37","doi-asserted-by":"publisher","first-page":"10125","DOI":"10.1073\/pnas.0802331105","volume":"105","author":"N Kimblin","year":"2008","unstructured":"Kimblin N, Peters N, Debrabant A, Secundino N, Egen J, Lawyer P et al. Quantification of the infectious dose of Leishmania major transmitted to the skin by single sand flies. Proc Natl Acad Sci USA 2008; 105: 10125\u201310130.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2015351_CR38","doi-asserted-by":"publisher","first-page":"6620","DOI":"10.1128\/IAI.73.10.6620-6628.2005","volume":"73","author":"S Bertholet","year":"2005","unstructured":"Bertholet S, Debrabant A, Afrin F, Caler E, Mendez S, Tabbara KS et al. Antigen requirements for efficient priming of CD8+ T cells by Leishmania major-infected dendritic cells. Infect Immun 2005; 73: 6620\u20136628.","journal-title":"Infect Immun"},{"key":"BFcddis2015351_CR39","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1128\/IAI.73.2.695-702.2005","volume":"73","author":"JP Saeij","year":"2005","unstructured":"Saeij JP, Boyle JP, Grigg ME, Arrizabalaga G, Boothroyd JC . Bioluminescence imaging of Toxoplasma gondii infection in living mice reveals dramatic differences between strains. Infect Immun 2005; 73: 695\u2013702.","journal-title":"Infect Immun"},{"key":"BFcddis2015351_CR40","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/S0022-1759(96)00117-2","volume":"199","author":"Y Belkaid","year":"1996","unstructured":"Belkaid Y, Jouin H, Milon G . A method to recover, enumerate and identify lymphomyeloid cells present in an inflammatory dermal site: a study in laboratory mice. J Immunol Methods 1996; 199: 5\u201325.","journal-title":"J Immunol Methods"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2015351.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2015351","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2015351.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T10:13:47Z","timestamp":1672913627000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2015351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,10]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["BFcddis2015351"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2015.351","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,10]]},"assertion":[{"value":"11 May 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 November 2015","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}