PARP1-cGAS-NF-κB pathway of proinflammatory macrophage activation by extracellular vesicles released during Trypanosoma cruzi infection and Chagas disease.
- 作者列表："Choudhuri S","Garg NJ
: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.
: 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。
METHODS:OBJECTIVE:There has been debate on the importance and pathophysiologic effects of the dynamic subaortic pressure gradient in hypertrophic obstructive cardiomyopathy. The study was conducted to elucidate the hemodynamic abnormalities associated with the dynamic pressure gradient in hypertrophic obstructive cardiomyopathy. METHODS:Eight patients with hypertrophic obstructive cardiomyopathy and 7 patients with valvular aortic stenosis underwent a detailed hemodynamic study of pressure flow relationships before and after myectomy or aortic valve replacement during operation. RESULTS:In aortic stenosis, the increased gradient after premature ventricular contraction was associated with an increase in peak flow (325 ± 122 mL/s to 428 ± 147 mL/s, P = .002) and stroke volume (75.0 ± 27.3 mL to 88.0 ± 24.0 mL, P = .004), but in hypertrophic obstructive cardiomyopathy peak flow remained unchanged (289 ± 79 mL/s to 299 ± 85 mL/s, P = .334) and stroke volume decreased (45.9 ± 18.7 mL to 38.4 ± 14.4 mL, P = .04) on the postpremature ventricular contraction beat. After myectomy, the capacity to augment stroke volume on the postpremature ventricular contraction beats was restored in patients with hypertrophic obstructive cardiomyopathy (45.6 ± 14.4 mL to 54.4 ± 11.8 mL, P = .002). CONCLUSIONS:The pressure flow relationship in hypertrophic obstructive cardiomyopathy supports the concept of true obstruction to outflow, with a low but continued flow during late systole, when the ventricular-aortic pressure gradient is the highest. Septal myectomy can abolish obstruction and restore the ability to augment stroke volume, which may explain the mechanism of symptomatic improvement after operation.
METHODS:INTRODUCTION:Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase, has altered the treatment perspective of chronic lymphocytic leukemia and showed modest activity against several types of non-Hodgkin's lymphomas. According to phase studies and real-world data, reported serious adverse effects included atrial fibrillation, diarrhea, and bleeding diathesis. However, heart failure was not reported to be a probable adverse effect linked with ibrutinib. CASE REPORT:In this paper, we present a 66-year-old female chronic lymphocytic leukemia patient who developed significant and symptomatic left ventricular dysfunction at the 13th month of ibrutinib treatment. MANAGEMENT AND OUTCOME:Following cessation of ibrutinib, ejection fraction and clinical findings of the left ventricular dysfunction alleviated. DISCUSSION:Although the use of ibrutinib is generally well tolerated, cardiac functions should be monitored occasionally in all patients.
METHODS:OBJECTIVES:The slope in the preload recruitable stroke work relationship is a highly linear, load-insensitive contractile parameter. However, the perioperative change of the slope has not been reported before. We examined the perioperative slope from a steady-state single beat in patients with functional mitral regurgitation and assessed the correlation with brain natriuretic peptide (BNP) levels. METHODS:The study included 16 patients with non-ischemic dilated cardiomyopathy and refractory heart failure: 10 patients underwent mitral valve plasty and left ventricular plasty (MVP + LVP group) and 6 patients who underwent mitral valve replacement and papillary muscle tugging approximation (MVR + PMTA group). The left ventricular ejection fraction was assessed by the modified Simpson method; the slope was assessed by the single-beat technique using transthoracic echocardiography. BNP levels were measured by chemiluminescent immunoassay. RESULTS:The left ventricular ejection fraction and slope did not significantly change from pre- to early post-surgery in the MVP + LVP group. Both the left ventricular ejection fraction and slope significantly increased 6 months after surgery in the MVR + PMTA group. Postoperative BNP level was low in the MVR + PMTA group. While the postoperative left ventricular ejection fraction did not correlate with BNP levels, the postoperative slope significantly correlated with BNP level after surgery in the MVP + LVP group and in the total functional mitral regurgitation group. CONCLUSIONS:The change of slope was dependent on surgical procedures. In functional mitral regurgitation, the slope may be a more sensitive parameter in reflecting the left ventricular contractile function than the left ventricular ejection fraction.