title: Toll-like receptor 9 signaling in dendritic cells regulates neutrophil recruitment to inflammatory foci following Leishmania infantum infection.
abstract: Leishmania infantum is a protozoan parasite that causes visceral leishmaniasis (VL). This infection triggers dendritic cell (DC) activation through the recognition of microbial products by Toll-like receptors (TLRs). Among the TLRs, TLR9 is required for DC activation by different Leishmania species. We demonstrated that TLR9 is upregulated in vitro and in vivo during infection. We show that C57BL/6 mice deficient in TLR9 expression (TLR9(-/-) mice) are more susceptible to infection and display higher parasite numbers in the spleen and liver. The increased susceptibility of TLR9(-/-) mice was due to the impaired recruitment of neutrophils to the infection foci associated with reduced levels of neutrophil chemoattractants released by DCs in the target organs. Moreover, both Th1 and Th17 cells were also committed in TLR9(-/-) mice. TLR9-dependent neutrophil recruitment is mediated via the MyD88 signaling pathway but is TIR domain-containing adapter-inducing interferon beta (TRIF) independent. Furthermore, L. infantum failed to activate both plasmacytoid and myeloid DCs from TLR9(-/-) mice, which presented reduced surface costimulatory molecule expression and chemokine release. Interestingly, neutrophil chemotaxis was affected both in vitro and in vivo when DCs were derived from TLR9(-/-) mice. Our results suggest that TLR9 plays a critical role in neutrophil recruitment during the protective response against L. infantum infection that could be associated with DC activation.
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Laís
authors.initials: L
authors.lastname: Sacramento
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Trevelin
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Manuela S
authors.initials: MS
authors.lastname: Nascimento
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Djalma S
authors.initials: DS
authors.lastname: Lima-Jùnior
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Diego L
authors.initials: DL
authors.lastname: Costa
authors.affiliation: Center for Biology and Health Sciences, Federal University of Sergipe, Aracaju, SE, Brazil.
authors.forename: Roque P
authors.initials: RP
authors.lastname: Almeida
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil jsdsilva@fmrp.usp.br vcarregaro@usp.br.
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil jsdsilva@fmrp.usp.br vcarregaro@usp.br.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Carregaro
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D018314:Leishmania infantum / Q000276:immunology* / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; D051217:Toll-Like Receptor 9; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C495370:Tlr9 protein, mouse