HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis.
Sci Rep
; 8(1): 3500, 2018 02 22.
Article
em En
| MEDLINE
| ID: mdl-29472618
ABSTRACT
Inflammation, although responsible for controlling infection, is often associated with the pathogenesis of chronic diseases. Leishmania donovani, the causative agent of visceral leishmaniasis, induces a strong inflammatory response that leads to splenomegaly and ultimately immune suppression. Inflamed tissues are typically characterized by low levels of oxygen, a microenvironment that triggers the hypoxia-inducible transcription factor 1α (HIF-1α). Although HIF-1α plays an integral role in dendritic cell function, its involvement in the generation of protective Th1 responses against Leishmania has not yet been studied. Here we demonstrate that HIF-1α inhibits IL-12 production in dendritic cells, limiting therefore Th1 cell development. Indeed, depletion of HIF-1α in CD11c+ cells resulted in higher and sustained expression of IL-12 and complete abrogation of IL-10. Moreover, CD11c-specific HIF-1α-deficient mice showed higher frequencies of IFN-γ-producing CD4 T cells in the spleen and bone marrow and, consequently, a significantly reduced parasite burden in both organs. Taken together, our results suggest that HIF-1α expression in dendritic cells largely contributes to the establishment of persistent Leishmania infection and may therefore represent a possible therapeutic target.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
2_ODS3
/
3_ND
Problema de saúde:
2_enfermedades_transmissibles
/
3_zoonosis
Assunto principal:
Leishmania donovani
/
Subunidade alfa do Fator 1 Induzível por Hipóxia
/
Inflamação
/
Leishmaniose Visceral
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Canadá