2. Academic Validation
  3. Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells

Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells

  • Cell Metab. 2024 Mar 5;36(3):484-497.e6. doi: 10.1016/j.cmet.2024.01.008.
Theresa Ramalho 1,  Patricia A Assis 2,  Ogooluwa Ojelabi 2,  Lin Tan 3,  Brener Carvalho 4,  Luiz Gardinassi 5,  Osvaldo Campos 6,  Philip L Lorenzi 3,  Katherine A Fitzgerald 2,  Cole Haynes 7,  Douglas T Golenbock 2,  Ricardo T Gazzinelli 8
Affiliations

Affiliations

  • 1 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. Electronic address: [email protected].
  • 2 Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 3 Department of Bioinformatics and Computational Biology, University of Texas MD Cancer Center, Houston, TX, USA.
  • 4 Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
  • 5 Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil.
  • 6 Plataforma de Medicina Translacional, Fundação Oswaldo Cruz/Faculdade de Medicina de Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil.
  • 7 Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 8 Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil; Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic address: [email protected].
PMID: 38325373 DOI: 10.1016/j.cmet.2024.01.008
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.

Keywords

PD-1; PD-L1; Plasmodium chabaudi; TCA cycle; cGAS-STING; immuno checkpoint markers; inate immunity; itaconate; itaconic acid; lymphocytes; malaria; metabolism; methylenesuccinic acid; mitochondria; mitochondrial DNA; monocyte-derived dendritic cells; mtDNA.

Figures