Medina Tiago Silva, Oliveira Gabriela Gonçalves, Silva Maria Cláudia, David Bruna Araújo, Silva Grace Kelly, Fonseca Denise Morais, Sesti-Costa Renata, Frade Amanda Farage, Baron Monique Andrade, Ianni Barbara, Pereira Alexandre Costa, Chevillard Christophe, Cunha-Neto Edécio, Marin-Neto José Antonio, Silva João Santana
Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Medical School/Heart Institute, University of São Paulo, São Paulo, Brazil.
Front Immunol. 2017 Sep 26;8:1213. doi: 10.3389/fimmu.2017.01213. eCollection 2017.
The identification of anti-inflammatory mediators can reveal important targetable molecules capable of counterbalancing -induced myocarditis. Composed of Ebi3 and IL-27p28 subunits, IL-27 is produced by myeloid cells and is able to suppress inflammation by inducing IL-10-producing Tr1 cells, thus emerging as a potential candidate to ameliorate cardiac inflammation induced by . Although IL-27 has been extensively characterized as a suppressive cytokine that prevents liver immunopathogenesis after infection, the mechanisms underlying its effects on -induced myocarditis remain largely unknown. Here, wild-type (WT) and Ebi3-deficient animals were intraperitoneally infected with trypomastigotes of Y strain and used to evaluate the potential anti-inflammatory properties of Ebi3 during infection. The survival rates of mice were daily recorded, the frequency of inflammatory cells was analyzed by flow cytometry and inflammatory mediators were measured by ELISA, real-time PCR and PCR array. We reported that -induced myocarditis was prevented by Ebi3. Stressors mainly recognized by TLR2 and TLR4 receptors on myeloid cells were essential to trigger IL-27p28 production. In addition, Ebi3 regulated IFN-γ-mediated myocarditis by promoting an anti-inflammatory environment through IL-10, which was most likely produced by Tr1 cells rather than classical regulatory T cells (Tregs), in the heart tissue of -infected animals. Furthermore, IFN-γ blockade ameliorated the host survival without compromising the parasite control in the bloodstream. In humans, IL-27p28 was correlated with cardiac protection during Chagas disease. Patients with mild clinical forms of the disease produced high levels of IL-27p28, whereas lower levels were found in those with severe forms. In addition, polymorphic sites at Ebi3 gene were associated with severe cardiomyopathy in patients with Chagas disease. Collectively, we describe a novel regulatory mechanism where Ebi3 dampens cardiac inflammation by modulating the overproduction of IFN-γ, the culprit of Chagas disease cardiomyopathy.
抗炎介质的鉴定可以揭示能够对抗锥虫诱导的心肌炎的重要可靶向分子。IL-27由Ebi3和IL-27p28亚基组成，由髓样细胞产生，能够通过诱导产生IL-10的Tr1细胞来抑制炎症，因此成为改善锥虫诱导的心脏炎症的潜在候选者。尽管IL-27已被广泛表征为一种抑制性细胞因子，可预防感染后肝脏的免疫病理发生，但其对锥虫诱导的心肌炎的作用机制仍 largely未知。在此，野生型（WT）和Ebi3缺陷动物经腹腔感染Y株锥鞭毛体，并用于评估感染期间Ebi3的潜在抗炎特性。每天记录小鼠的存活率，通过流式细胞术分析炎性细胞的频率，并通过ELISA、实时PCR和PCR阵列测量炎性介质。我们报告Ebi3可预防锥虫诱导的心肌炎。髓样细胞上主要由TLR2和TLR4受体识别的应激源对于触发IL-27p28的产生至关重要。此外，Ebi3通过IL-10促进抗炎环境来调节IFN-γ介导的心肌炎，IL-10很可能由感染锥虫的动物心脏组织中的Tr1细胞而非经典调节性T细胞（Tregs）产生。此外，IFN-γ阻断改善了宿主存活，而不影响血液中寄生虫的控制。在人类中，IL-27p28与恰加斯病期间的心脏保护相关。疾病临床症状较轻的患者产生高水平的IL-27p28，而症状严重的患者水平较低。此外，Ebi3基因的多态性位点与恰加斯病患者的严重心肌病相关。总体而言，我们描述了一种新的调节机制，其中Ebi3通过调节IFN-γ的过度产生来减轻心脏炎症，IFN-γ是恰加斯病心肌病的罪魁祸首。
