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1.
Front Immunol ; 10: 3071, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32038622

RESUMO

Persistent Leishmania donovani infection is characterized by chronic inflammation, immune suppression, and splenomegaly. We have previously reported that the transcription factor interferon regulatory factor 5 (IRF-5) is largely responsible for inducing the inflammatory response and maintaining protective Th1 cells following L. donovani inoculation in mice. However, the cellular source responsible for these effects is yet unknown. In this study, we investigated the role of IRF-5 in myeloid cells during experimental visceral leishmaniasis (VL). First, we show that the LysM-Cre mouse model is not suited for investigating gene expression in splenic myeloid cells during experimental VL. Using the Cd11c-Cre mouse model, we demonstrate that Irf5 expression in CD11c+ cells (monocytes, dendritic cells, activated macrophages) is essential for inducing splenomegaly and for recruiting myeloid cells to the spleen, but it is not required for the development or maintenance of parasite-specific IFNγ-producing CD4 T cells. CD11c-specific Irf5-/- mice are more resistant to L. donovani infection, suggesting that the induction of splenomegaly is detrimental to the host.


Assuntos
Fatores Reguladores de Interferon/imunologia , Leishmaniose Visceral/imunologia , Células Mieloides/imunologia , Esplenomegalia/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Humanos , Fatores Reguladores de Interferon/genética , Interferon gama/genética , Interferon gama/imunologia , Leishmania donovani/fisiologia , Leishmaniose Visceral/genética , Leishmaniose Visceral/parasitologia , Camundongos , Baço/imunologia , Baço/parasitologia , Esplenomegalia/genética , Esplenomegalia/parasitologia
2.
Cell Rep ; 15(11): 2427-37, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27264176

RESUMO

Participation of B cells in the immune response by various antibody-independent mechanisms has recently been uncovered. B cells producing cytokines have been described for several infections and appear to regulate the adaptive immune response. B cell activation by Leishmania donovani results in disease exacerbation. How Leishmania activates B cells is still unknown. We show that L. donovani amastigotes activate B cells by triggering endosomal TLRs; this activation leads to the induction of various cytokines. Cytokine expression is completely abrogated in B cells from Ifnar(-/-) mice upon exposure to L. donovani, suggesting an involvement of IFN-I in a positive feedback loop. IFN-I also appears to enhance the expression of endosomal TLRs following exposure to L. donovani. Cell-specific ablation of endosomal TLR signaling in B cells revealed that innate B cell activation by L. donovani is responsible for disease exacerbation through IL-10 and IFN-I production and for the promotion of hypergammaglobulinemia.


Assuntos
Linfócitos B/imunologia , Progressão da Doença , Hipergamaglobulinemia/imunologia , Imunidade Inata , Leishmania donovani/fisiologia , Leishmaniose/imunologia , Leishmaniose/parasitologia , Ativação Linfocitária/imunologia , Animais , Linfócitos B/parasitologia , Endossomos/metabolismo , Hipergamaglobulinemia/complicações , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Leishmaniose/genética , Leishmaniose/patologia , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/metabolismo , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Baço/patologia , Células Th1/imunologia , Receptores Toll-Like/metabolismo , Regulação para Cima/genética
3.
PLoS Pathog ; 11(6): e1004938, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26046638

RESUMO

Inflammation is known to be necessary for promoting, sustaining, and tuning CD8+ T cell responses. Following experimental Leishmania donovani infection, the inflammatory response is mainly induced by the transcription factor IRF-5. IRF-5 is responsible for the activation of several genes encoding key pro-inflammatory cytokines, such as IL-6 and TNF. Here, we investigate the role of IRF-5-mediated inflammation in regulating antigen-specific CD8+ T cell responses during L. donovani infection. Our data demonstrate that the inflammatory response induced by IRF-5 limits CD8+ T cell expansion and induces HIF-1α in dendritic cells. Ablation of HIF-1α in CD11c+ cells resulted into a higher frequency of short-lived effector cells (SLEC), enhanced CD8+ T cell expansion, and increased IL-12 expression by splenic DCs. Moreover, mice with a targeted depletion of HIF-1α in CD11c+ cells had a significantly lower splenic parasite burden, suggesting that induction of HIF-1α may represent an immune evasive mechanism adopted by Leishmania parasites to establish persistent infections.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Evasão da Resposta Imune/imunologia , Fatores Reguladores de Interferon/imunologia , Leishmaniose Visceral/imunologia , Transferência Adotiva , Animais , Western Blotting , Modelos Animais de Doenças , Citometria de Fluxo , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Inflamação/imunologia , Leishmania donovani , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Reação em Cadeia da Polimerase em Tempo Real
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