Author | Ramalho, Theresa | |
Author | Assis, Patricia A | |
Author | Ojelabi, Ogooluwa | |
Author | Tan, Lin | |
Author | Carvalho, Brener | |
Author | Gardinassi, Luiz | |
Author | Campos, Osvaldo | |
Author | Lorenzi, Philip L | |
Author | Fitzgerald, Katherine A | |
Author | Haynes, Cole | |
Author | Golenbock, Douglas Taylor | |
Author | Gazzinelli, Ricardo Tostes | |
Access date | 2024-04-18T18:02:07Z | |
Available date | 2024-04-18T18:02:07Z | |
Document date | 2024 | |
Citation | RAMALHO, Theresa et al. Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells. Cell Metabolism, v. 36, n. 3, p. 484-497.e6, 2024. doi.org/10.1016/j.cmet.2024.01.008. | en_US |
ISSN | 1550-4131 | en_US |
URI | https://www.arca.fiocruz.br/handle/icict/63576 | |
Language | eng | en_US |
Publisher | Cell Press | en_US |
Rights | restricted access | en_US |
Title | Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells. | en_US |
Type | Article | en_US |
Abstract | Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy. | en_US |
Affilliation | Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA/Department of Molecular Cell and Cancer Biology. University of Massachusetts Chan Medical School. Worcester, MA, USA | en_US |
Affilliation | Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA. | en_US |
Affilliation | Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA. | en_US |
Affilliation | Department of Bioinformatics and Computational Biology. University of Texas MD Cancer Center. Houston, TX, USA. | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil. | en_US |
Affilliation | Universidade Federal de Goiás. Instituto de Patologia Tropical e Saúde Pública. Goiânia, GO, Brazil. | en_US |
Affilliation | Fundação Oswaldo Cruz. Plataforma de Medicina Translacional. . Ribeirao Preto, SP, Brazil/Faculdade de Medicina de Ribeirao Preto. Ribeirao Preto, SP, Brazil. | en_US |
Affilliation | Department of Bioinformatics and Computational Biology. University of Texas MD Cancer Center. Houston, TX, USA. | en_US |
Affilliation | Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA. | en_US |
Affilliation | Department of Molecular Cell and Cancer Biology. University of Massachusetts Chan Medical School. Worcester, MA, USA. | en_US |
Affilliation | Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA. | en_US |
Affilliation | Department of Medicine. University of Massachusetts Chan Medical School. Worcester, MA, USA/ Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil/Universidade Federal de Minas Gerais. Centro de Tecnologia de Vacinas. Belo Horizonte, MG, Brazil. | en_US |
Subject | PD-1 | en_US |
Subject | PD-L1 | en_US |
Subject | Plasmodium chabaudi | en_US |
Subject | TCA cycle | en_US |
Subject | cGAS-STING | en_US |
Subject | immuno checkpoint markers | en_US |
Subject | inate immunity | en_US |
Subject | itaconate | en_US |
Subject | itaconic acid | en_US |
Subject | lymphocytes | en_US |
Subject | malaria | en_US |
Subject | metabolism | en_US |
Subject | methylenesuccinic acid | en_US |
Subject | mitochondria | en_US |
Subject | mitochondrial DNA | en_US |
Subject | monocyte-derived dendritic cells | en_US |
Subject | mtDNA | en_US |
Embargo date | 2030-12-31 | |