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PARP1-cGAS-NF-κB pathway of proinflammatory macrophage activation by extracellular vesicles released during Trypanosoma cruzi infection and Chagas disease.
- Source :
-
PLoS pathogens [PLoS Pathog] 2020 Apr 21; Vol. 16 (4), pp. e1008474. Date of Electronic Publication: 2020 Apr 21 (Print Publication: 2020). - Publication Year :
- 2020
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Abstract
- Trypanosoma cruzi (T. cruzi) is the etiological agent of Chagas cardiomyopathy. In the present study, we investigated the role of extracellular vesicles (Ev) in shaping the macrophage (Mφ) response in progressive Chagas disease (CD). We purified T. cruzi Ev (TcEv) from axenic parasite cultures, and T. cruzi-induced Ev (TEv) from the supernatants of infected cells and plasma of acutely and chronically infected wild-type and Parp1-/- mice. Cultured (Raw 264.7) and bone-marrow Mφ responded to TcEV and TEv with a profound increase in the expression and release of TNF-α, IL-6, and IL-1β cytokines. TEv produced by both immune (Mφ) and non-immune (muscle) cells were proinflammatory. Chemical inhibition or genetic deletion of PARP1 (a DNA repair enzyme) significantly depressed the TEv-induced transcriptional and translational activation of proinflammatory Mφ response. Oxidized DNA encapsulated by TEv was necessary for PARP1-dependent proinflammatory Mφ response. Inhibition studies suggested that DNA-sensing innate immune receptors (cGAS>>TLR9) synergized with PARP1 in signaling the NFκB activation, and inhibition of PARP1 and cGAS resulted in >80% inhibition of TEv-induced NFκB activity. Histochemical studies showed intense inflammatory infiltrate associated with profound increase in CD11b+CD68+TNF-α+ Mφ in the myocardium of CD wild-type mice. In comparison, chronically infected Parp1-/- mice exhibited low-to-moderate tissue inflammation, >80% decline in myocardial infiltration of TNF-α+ Mφ, and no change in immunoregulatory IL-10+ Mφ. We conclude that oxidized DNA released with TEv signal the PARP1-cGAS-NF-κB pathway of proinflammatory Mφ activation and worsens the chronic inflammatory pathology in CD. Small molecule antagonists of PARP1-cGAS signaling pathway would potentially be useful in reprogramming the Mφ activation and controlling the chronic inflammation in CD.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Chagas Cardiomyopathy immunology
Chagas Cardiomyopathy metabolism
Cytokines immunology
Cytokines metabolism
Female
Interleukin-1beta immunology
Interleukin-1beta metabolism
Interleukin-6 immunology
Interleukin-6 metabolism
Macrophages metabolism
Male
Mice
Mice, Knockout
NF-kappa B immunology
Nucleotidyltransferases immunology
Poly (ADP-Ribose) Polymerase-1 immunology
RAW 264.7 Cells
Reactive Oxygen Species metabolism
Signal Transduction immunology
Trypanosoma cruzi metabolism
Trypanosoma cruzi pathogenicity
Tumor Necrosis Factor-alpha immunology
Tumor Necrosis Factor-alpha metabolism
Chagas Disease metabolism
Extracellular Vesicles metabolism
Macrophage Activation immunology
Macrophages immunology
NF-kappa B metabolism
Nucleotidyltransferases metabolism
Poly (ADP-Ribose) Polymerase-1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 16
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 32315358
- Full Text :
- https://doi.org/10.1371/journal.ppat.1008474