{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T18:36:01Z","timestamp":1778524561988,"version":"3.51.4"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["166166\/2014"],"award-info":[{"award-number":["166166\/2014"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2017\/02998-0, 2014\/13324-1, 2016\/14657-0, 2018\/21708-5, 2016\/10446-4, 2013\/04088-0, 2004\/08868-0"],"award-info":[{"award-number":["2017\/02998-0, 2014\/13324-1, 2016\/14657-0, 2018\/21708-5, 2016\/10446-4, 2013\/04088-0, 2004\/08868-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The protozoan parasite<jats:italic>Toxoplasma gondii<\/jats:italic>modulates host cell responses to favor its success in the early stage of infections by secreting proteins from its apical organelles. Some of these proteins, including microneme proteins (MICs) 1 and 4, trigger pro-inflammatory host cell responses. The lectins MIC1 and MIC4 interact with N-linked glycans on TLR2 and TLR4, activating NF-\u03baB and producing IL-12, TNF-\u03b1, and IL-6. Interestingly, MIC1 and MIC4 also trigger secretion of the anti-inflammatory cytokine IL-10 through mechanisms as yet unknown. Herein, we show that the ability of these MICs to induce macrophages to produce IL-10 depends on TLR4 internalization from the cell surface. Macrophages subjected to blockade of endocytosis by Dynasore continued to release TNF-\u03b1, but failed to produce IL-10, in response to MIC1 or MIC4 exposure. Similarly, IL-10 was not produced by Dynasore-conditioned<jats:italic>T. gondii<\/jats:italic>-infected macrophages. Furthermore, MIC1- or MIC4-stimulated macrophages gained transient tolerance to LPS. We report a previously undiscovered mechanism by which well-defined<jats:italic>T. gondii<\/jats:italic>components inhibit a host inflammatory response.<\/jats:p>","DOI":"10.3389\/fimmu.2021.655371","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T04:42:51Z","timestamp":1618202571000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Microneme Proteins 1 and 4 From Toxoplasma gondii Induce IL-10 Production by Macrophages Through TLR4 Endocytosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Rafael","family":"Ricci-Azevedo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavia Costa","family":"Mendon\u00e7a-Natividade","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Carolina","family":"Santana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Alcoforado Diniz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Cristina","family":"Roque-Barreira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,12]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1201\/9781420092370","volume-title":"Toxoplasmosis of Animals and Humans","author":"Dubey","year":"2016"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)16412-X","article-title":"Toxoplasmosis","volume":"363","author":"Montoya","year":"2004","journal-title":"The Lancet"},{"key":"B3","article-title":"Toxoplasma gondii","volume-title":"Foodborne Parasites","author":"Hill","year":"2018"},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511527005.008","article-title":"Toxoplasma infection in immunosuppressed (HIV-negative) patients","volume-title":"Toxoplasmosis: A Comprehensive Clinical Guide","author":"Wreghitt","year":"2001"},{"key":"B5","article-title":"Sequential protein secretion from three distinct organelles of Toxoplasma gondii accompanies invasion of human fibroblasts","volume":"73","author":"Carruthers","year":"1997","journal-title":"Eur J Cell Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2858","article-title":"Modulation of innate immunity by Toxoplasma gondii virulence effectors","volume":"10","author":"Hunter","year":"2012","journal-title":"Nat Rev Microbiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.152.3.563","article-title":"Identification and characterization of an escorter for two secretory adhesins in Toxoplasma gondii","volume":"153","author":"Reiss","year":"2001","journal-title":"J Cell Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaa072","article-title":"A sialic acid-binding protein SABP1 of toxoplasma gondii mediates host cell attachment and invasion","volume":"222","author":"Xing","year":"2020","journal-title":"J Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2006.08.002","article-title":"Toxoplasma gondii and subversion of the immune system","volume":"22","author":"Buzoni-Gatel","year":"2006","journal-title":"Trends Parasitol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1126\/science.1109893","article-title":"Immunology: TLR11 activation of dendritic cells by a protozoan profilin-like protein","volume":"308","author":"Yarovinsky","year":"2005","journal-title":"Science (80)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.09.016","article-title":"Recognition of Profilin by Toll-like Receptor 12 Is Critical for Host Resistance to Toxoplasma gondii","volume":"11","author":"Koblansky","year":"2013","journal-title":"Immunity"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nri3598","article-title":"Innate immunity to Toxoplasma gondii infection","volume":"14","author":"Yarovinsky","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.2.1129","article-title":"Activation of TLR2 and TLR4 by Glycosylphosphatidylinositols Derived from Toxoplasma gondii","volume":"179","author":"Debierre-Grockiego","year":"2007","journal-title":"J Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.bbrc.2004.07.205","article-title":"Toxoplasma gondii-derived heat shock protein 70 stimulates the maturation of human monocyte-derived dendritic cells","volume":"322","author":"Kang","year":"2004","journal-title":"Biochem Biophys Res Commun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130103","article-title":"A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation","volume":"210","author":"Braun","year":"2013","journal-title":"J Exp Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008572","article-title":"Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity","author":"Mercer","year":"2020","journal-title":"PloS Pathog"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/11.7.541","article-title":"Toxoplasma gondii micronemal protein MIC1 is a lactose-binding lectin","volume":"11","author":"Louren\u00e7o","year":"2001","journal-title":"Glycobiology"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2005.11.013","article-title":"Immunization with MIC1 and MIC4 induces protective immunity against Toxoplasma gondii","volume":"8","author":"Louren\u00e7o","year":"2006","journal-title":"Microbes Infect"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e1007871","DOI":"10.1371\/journal.ppat.1007871","article-title":"The lectin-specific activity of Toxoplasma gondii microneme proteins 1 and 4 binds Toll-like receptor 2 and 4 N-glycans to regulate innate immune priming","volume":"15","author":"Sardinha-Silva","year":"2019","journal-title":"PloS Pathog"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20205001","article-title":"Receptor heterodimerization and co-receptor engagement in TLR2 activation induced by MIC1 and MIC4 from Toxoplasma gondii","volume":"20","author":"Mendon\u00e7a-Natividade","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004120","article-title":"Multimeric Assembly of Host-Pathogen Adhesion Complexes Involved in Apicomplexan Invasion","volume":"10","author":"Paing","year":"2014","journal-title":"PloS Pathog"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008294200","article-title":"The Toxoplasma Micronemal Protein MIC4 Is an Adhesin Composed of Six Conserved Apple Domains","volume":"276","author":"Brecht","year":"2001","journal-title":"J Biol Chem"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.325928","article-title":"Galactose recognition by the apicomplexan parasite Toxoplasma gondii","volume":"287","author":"Marchant","year":"2012","journal-title":"J Biol Chem"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01820","article-title":"Targeting and recognition of toll-like receptors by plant and pathogen lectins","volume":"8","author":"Ricci-Azevedo","year":"2017","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/science.3128869","article-title":"Interferon-\u03b3: The major mediator of resistance against Toxoplasma gondii","volume":"240","author":"Suzuki","year":"1988","journal-title":"Science (80)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.imlet.2008.05.007","article-title":"Toll-like receptors and their role in host resistance to Toxoplasma gondii","volume":"119","author":"Yarovinsky","year":"2008","journal-title":"Immunol Lett"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2010.8","article-title":"IL-10 production by CD4+ effector T cells: A mechanism for self-regulation","volume":"3","author":"Jankovic","year":"2010","journal-title":"Mucosal Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.9.5771","article-title":"IL-10: The Master Regulator of Immunity\u00a0to Infection","volume":"180","author":"Couper","year":"2008","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"crossref","first-page":"798","DOI":"10.4049\/jimmunol.157.2.798","article-title":"In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha","volume":"157","author":"Gazzinelli","year":"1996","journal-title":"J Immunol"},{"key":"B30","first-page":"2132","article-title":"Production and characterization of MIC1: A lectin from toxoplasma gondii","volume-title":"LecQn PurificaQon and Analysis. Methods in Molecular Biology","author":"Costa Mendon\u00e7a-Natividade","year":"2020"},{"key":"B31","doi-asserted-by":"publisher","first-page":"20c.1.1","DOI":"10.1002\/cpmc.26","article-title":"Toxoplasma gondii: Laboratory maintenance and growth","volume":"44","author":"Khan","year":"2017","journal-title":"Curr Protoc Microbiol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e15263","DOI":"10.1371\/journal.pone.0015263","article-title":"A Method for Generation of Bone Marrow-Derived Macrophages from Cryopreserved Mouse Bone Marrow Cells","volume":"5","author":"Marim","year":"2010","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00347","article-title":"Evolving Bacterial Envelopes and Plasticity of TLR2-Dependent Responses: Basic Research and Translational Opportunities","author":"Li","year":"2013","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/iai.58.8.2429-2437.1990","article-title":"Differential cytokine induction by doses of lipopolysaccharide and monophosphoryl lipid A that result in equivalent early endotoxin tolerance","author":"Henricson","year":"1990","journal-title":"Infect Immun"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202407","article-title":"Dissociation of Endotoxin Tolerance and Differentiation of Alternatively Activated Macrophages","volume":"190","author":"Rajaiah","year":"2013","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature05836","article-title":"Gene-specific control of inflammation by TLR-induced chromatin modifications","volume":"447","author":"Foster","year":"2007","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1424980112","article-title":"CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance","volume":"112","author":"Rajaiah","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.6.3712","article-title":"Toll-Like Receptor 2 Suppresses Immunity against Candida albicans through Induction of IL-10 and Regulatory T Cells","volume":"172","author":"Netea","year":"2004","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.8.4733","article-title":"A Toll-Like Receptor 2 Ligand Stimulates Th2 Responses In Vivo, via Induction of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and c-Fos in Dendritic Cells","volume":"172","author":"Dillon","year":"2004","journal-title":"J Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.02.014","article-title":"IFN-\u03b3 Suppresses IL-10 Production and Synergizes with TLR2 by Regulating GSK3 and CREB\/AP-1 Proteins","volume":"24","author":"Hu","year":"2006","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.11.7551","article-title":"Macrophages and Myeloid Dendritic Cells, but Not Plasmacytoid Dendritic Cells, Produce IL-10 in Response to MyD88- and TRIF-Dependent TLR Signals, and TLR-Independent Signals","volume":"177","author":"Boonstra","year":"2006","journal-title":"J Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nri2711","article-title":"The regulation of IL-10 production by immune cells","volume":"10","author":"Saraiva","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.11.6705","article-title":"Cutting Edge: Involvement of the Type I IFN Production and Signaling Pathway in Lipopolysaccharide-Induced IL-10 Production","volume":"178","author":"Chang","year":"2007","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2426","article-title":"The p110\u03b4 isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock","volume":"13","author":"Aksoy","year":"2012","journal-title":"Nat Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jneuroim.2005.04.018","article-title":"A critical role for IL-10 in limiting inflammation during toxoplasmic encephalitis","volume":"165","author":"Wilson","year":"2005","journal-title":"J Neuroimmunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2016.05.008","article-title":"Induction of IL-10-producing regulatory B cells following Toxoplasma gondii infection is important to the cyst formation","volume":"7","author":"Jeong","year":"2016","journal-title":"Biochem Biophys Rep"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1220272110","article-title":"Motile invaded neutrophils in the small intestine of Toxoplasma gondii-infected mice reveal a potential mechanism for parasite spread","volume":"10","author":"Coombes","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e0143087","DOI":"10.1371\/journal.pone.0143087","article-title":"Vaccination with recombinant microneme proteins confers protection against experimental toxoplasmosis in mice","volume":"10","author":"Pinzan","year":"2015","journal-title":"PloS One"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.655371\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T23:31:38Z","timestamp":1698881498000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.655371\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,12]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2021.655371"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.655371","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,12]]},"article-number":"655371"}}