RESUMO
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.
Assuntos
Leishmania infantum/imunologia , Leishmaniose Visceral/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Receptor Toll-Like 9/imunologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Células Dendríticas/patologia , Feminino , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Leishmania infantum/patogenicidade , Leishmaniose Visceral/genética , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/patologia , Fígado/imunologia , Fígado/parasitologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Neutrófilos/parasitologia , Neutrófilos/patologia , Transdução de Sinais , Baço/imunologia , Baço/parasitologia , Baço/patologia , Células Th1/imunologia , Células Th1/parasitologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/parasitologia , Células Th17/patologia , Receptor Toll-Like 9/deficiência , Receptor Toll-Like 9/genéticaRESUMO
Here we identified B cells as a major source of rapid, innate-like production of interleukin 17 (IL-17) in vivo in response to infection with Trypanosoma cruzi. IL-17(+) B cells had a plasmablast phenotype, outnumbered cells of the TH17 subset of helper T cells and were required for an optimal response to this pathogen. With both mouse and human primary B cells, we found that exposure to parasite-derived trans-sialidase in vitro was sufficient to trigger modification of the cell-surface mucin CD45, which led to signaling dependent on the kinase Btk and production of IL-17A or IL-17F via a transcriptional program independent of the transcription factors RORγt and Ahr. Our combined data suggest that the generation of IL-17(+) B cells may be a previously unappreciated feature of innate immune responses required for pathogen control or IL-17-mediated autoimmunity.