%0 Journal Article
%T PARP1-cGAS-NF-¦ÊB pathway of proinflammatory macrophage activation by extracellular vesicles released during Trypanosoma cruzi infection and Chagas disease
%A Nisha Jain Garg
%A Subhadip Choudhuri
%J -
%D 2020
%R 10.1371/journal.ppat.1008474
%X 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 (M¦Õ) 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 M¦Õ responded to TcEV and TEv with a profound increase in the expression and release of TNF-¦Á, IL-6, and IL-1¦Â cytokines. TEv produced by both immune (M¦Õ) 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 M¦Õ response. Oxidized DNA encapsulated by TEv was necessary for PARP1-dependent proinflammatory M¦Õ response. Inhibition studies suggested that DNA-sensing innate immune receptors (cGAS>>TLR9) synergized with PARP1 in signaling the NF¦ÊB activation, and inhibition of PARP1 and cGAS resulted in >80% inhibition of TEv-induced NF¦ÊB activity. Histochemical studies showed intense inflammatory infiltrate associated with profound increase in CD11b+CD68+TNF-¦Á+ M¦Õ 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-¦Á+ M¦Õ, and no change in immunoregulatory IL-10+ M¦Õ. We conclude that oxidized DNA released with TEv signal the PARP1-cGAS-NF-¦ÊB pathway of proinflammatory M¦Õ activation and worsens the chronic inflammatory pathology in CD. Small molecule antagonists of PARP1-cGAS signaling pathway would potentially be useful in reprogramming the M¦Õ activation and controlling the chronic inflammation in CD
%K Trypanosoma cruzi
%K Cytokines
%K Chagas disease
%K Parasitic diseases
%K Macrophages
%K Gene expression
%K Inflammatory diseases
%K Transcription factors
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008474