HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis

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 suppressio...

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Autores principales:	Akil Hammami, Belma Melda Abidin, Krista M. Heinonen, Simona Stäger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/db28a9d99446473bb1a7cbda14e13b25
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spelling	oai:doaj.org-article:db28a9d99446473bb1a7cbda14e13b252021-12-02T16:08:03ZHIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis10.1038/s41598-018-21891-z2045-2322https://doaj.org/article/db28a9d99446473bb1a7cbda14e13b252018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21891-zhttps://doaj.org/toc/2045-2322Abstract 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.Akil HammamiBelma Melda AbidinKrista M. HeinonenSimona StägerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Akil Hammami Belma Melda Abidin Krista M. Heinonen Simona Stäger HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis
description	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.
format	article
author	Akil Hammami Belma Melda Abidin Krista M. Heinonen Simona Stäger
author_facet	Akil Hammami Belma Melda Abidin Krista M. Heinonen Simona Stäger
author_sort	Akil Hammami
title	HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis
title_short	HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis
title_full	HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis
title_fullStr	HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis
title_full_unstemmed	HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis
title_sort	hif-1α hampers dendritic cell function and th1 generation during chronic visceral leishmaniasis
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/db28a9d99446473bb1a7cbda14e13b25
work_keys_str_mv	AT akilhammami hif1ahampersdendriticcellfunctionandth1generationduringchronicvisceralleishmaniasis AT belmameldaabidin hif1ahampersdendriticcellfunctionandth1generationduringchronicvisceralleishmaniasis AT kristamheinonen hif1ahampersdendriticcellfunctionandth1generationduringchronicvisceralleishmaniasis AT simonastager hif1ahampersdendriticcellfunctionandth1generationduringchronicvisceralleishmaniasis
_version_	1718384687715450880

HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis

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