title: TLR2, TLR4 and Dectin-1 signalling in hematopoietic stem and progenitor cells determines the antifungal phenotype of the macrophages they produce.
abstract: TLRs represent an attractive target for the stimulation of myeloid cell production by HSPCs. We have previously demonstrated that HSPCs use TLR2 to sense Candida albicans in vivo and induce the production of macrophages. In this work, we used an in vitro model of HSPCs differentiation to investigate the functional consequences for macrophages of exposure of HSPCs to various PAMPs and C. albicans cells. Mouse HSPCs (Lin(-) cells) were cultured with M-CSF to induce macrophage differentiation, in the presence or absence of the following PRR agonists: Pam3CSK4 (TLR2 ligand), LPS (TLR4 ligand), depleted zymosan (which only activates Dectin-1), or C. albicans yeasts (which activate several PRRs, but principally TLR2 and Dectin-1). Our data show that these PAMPs differentially impact the anti-microbial function of the macrophages produced by the exposed HSPCs. Pure TLR2 and TLR4 ligands generate macrophages with a diminished ability to produce inflammatory cytokines. In contrast, HSPCs activation in response to C. albicans leads to the generation of macrophages that are better prepared to deal with the infection, as they produce higher amounts of inflammatory cytokines and have higher fungicidal capacity than control macrophages. Therefore, the tailored manipulation of the differentiation process may help to boost the innate immune response to infection.
authors.affiliation: Departamento de Microbiología y Ecología, Universitat de València, Burjassot, Spain; Departamento de Patología, Universitat de València, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Megías
authors.affiliation: Departamento de Microbiología y Ecología, Universitat de València, Burjassot, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Yáñez
authors.affiliation: Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA; Research Division of Immunology, Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Goodridge
authors.affiliation: Departamento de Microbiología y Ecología, Universitat de València, Burjassot, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gozalbo
authors.affiliation: Departamento de Microbiología y Ecología, Universitat de València, Burjassot, Spain. Electronic address: m.luisa.gil@uv.es.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Gil
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000276:immunology*; D002454:Cell Differentiation; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D037181:Lectins, C-Type / Q000378:metabolism*; D055666:Lipopeptides / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015054:Zymosan / Q000276:immunology; D000099181:Dectin-1
chemical_list: D037181:Lectins, C-Type; D055666:Lipopeptides; D008070:Lipopolysaccharides; D016173:Macrophage Colony-Stimulating Factor; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D015054:Zymosan; D000099181:Dectin-1; C508075:Pam(3)CSK(4) peptide; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse
keywords: Candida albicans; Dectin-1; Hematopoietic stem and progenitor cells; M-CSF; Macrophages; TLRs