Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells
Published by Elsevier Inc..
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.
| Errataetall: |
CommentIn: Cell Metab. 2024 Mar 5;36(3):457-458. - PMID 38447526 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
Cell metabolism - 36(2024), 3 vom: 05. März, Seite 484-497.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ramalho, Theresa [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.03.2024 Date Revised 20.03.2024 published: Print-Electronic CommentIn: Cell Metab. 2024 Mar 5;36(3):457-458. - PMID 38447526 Citation Status MEDLINE |
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| doi: |
10.1016/j.cmet.2024.01.008 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368146057 |
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| 500 | |a CommentIn: Cell Metab. 2024 Mar 5;36(3):457-458. - PMID 38447526 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Published by Elsevier Inc. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Assis, Patricia A |e verfasserin |4 aut | |
| 700 | 1 | |a Ojelabi, Ogooluwa |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Carvalho, Brener |e verfasserin |4 aut | |
| 700 | 1 | |a Gardinassi, Luiz |e verfasserin |4 aut | |
| 700 | 1 | |a Campos, Osvaldo |e verfasserin |4 aut | |
| 700 | 1 | |a Lorenzi, Philip L |e verfasserin |4 aut | |
| 700 | 1 | |a Fitzgerald, Katherine A |e verfasserin |4 aut | |
| 700 | 1 | |a Haynes, Cole |e verfasserin |4 aut | |
| 700 | 1 | |a Golenbock, Douglas T |e verfasserin |4 aut | |
| 700 | 1 | |a Gazzinelli, Ricardo T |e verfasserin |4 aut | |
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