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PARP1-cGAS-NF-κB pathway of proinflammatory macrophage activation by extracellular vesicles released during Trypanosoma cruzi infection and Chagas disease.

克氏锥虫感染和恰加斯病时释放的细胞外囊泡激活促炎巨噬细胞的parp1-cgas-nf-κ b途径。

  • 影响因子:6.02
  • DOI:10.1371/journal.ppat.1008474
  • 作者列表:"Choudhuri S","Garg NJ
  • 发表时间:2020-04-21
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.

摘要

: 克氏锥虫 (T. cruzi) 是恰加斯心肌病的病因。在本研究中,我们研究了细胞外囊泡 (Ev) 在形成进行性恰加斯病 (CD) 中巨噬细胞 (m φ) 反应中的作用。我们从无菌寄生虫培养物中纯化了T. cruzi Ev (TcEv),并从急性和慢性感染的野生型和Parp1-/-小鼠的感染细胞和血浆上清液中纯化了T. cruzi诱导的Ev (TEv)。培养的 (Raw 264.7) 和骨髓m φ 响应TcEV和TEv,TNF-α 、IL-6和IL-1β 细胞因子的表达和释放显著增加。由免疫 (m φ) 和非免疫 (肌肉) 细胞产生的TEv是促炎的。PARP1 (一种DNA修复酶) 的化学抑制或遗传缺失显著抑制了TEv诱导的促炎性m φ 反应的转录和翻译激活。TEv包裹的氧化DNA是PARP1-dependent促炎性m φ 反应所必需的。抑制研究表明,DNA感应天然免疫受体 (cGAS>TLR9) 与PARP1在信号转导nf κ b激活方面协同作用,并且抑制PARP1和cGAS导致TEv诱导的nf κ b活性的> 80% 抑制。组织化学研究显示在CD野生型小鼠的心肌中与CD11b + CD68 + TNF-α + m φ 的显著增加相关的强烈炎性浸润。相比之下,慢性感染的Parp1-/-小鼠表现出低至中度组织炎症,TNF-α + m φ 的心肌浸润下降> 80%,而免疫调节IL-10 + m φ 无变化。我们得出结论,TEv释放的氧化DNA为促炎性m φ 激活的parp1-cgas-nf-κ b途径发出信号,并恶化了CD的慢性炎症病理。PARP1-cGAS信号传导途径的小分子拮抗剂可能用于重新编程m φ 激活和控制CD的慢性炎症。

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心肌病方向

心肌病是一组异质性心肌疾病,由不同病因引起心脏机械和电活动的异常,表现为心室不适当的肥厚或扩张。严重心肌病会引起心血管性死亡或进展性心力衰竭。心肌病通常分为原发性心肌病和继发性心肌病,其中原发性心肌病包括扩张型心肌病、肥厚型心肌病、限制型心肌病、致心律失常性右室心肌病和未定型心肌病。继发性心肌病指心肌病是全身性疾病的一部分。

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