Imunologia Celular e Molecular, Instituto René Rachou, FIOCRUZ, Belo Horizonte, Brazil.
Laboratório de Biologia das Interações Celulares, Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Front Immunol. 2019 Apr 18;10:800. doi: 10.3389/fimmu.2019.00800. eCollection 2019.
Chagas cardiomyopathy is the main fibrosing myocarditis among known heart diseases. Development of cardiomyopathy has been related to extracellular matrix (ECM) remodeling, which are controlled by matrix metalloproteinases (MMPs) and cytokines, especially interleukin (IL)-1β. The convertion of 31KDa inactive precursor, the proIL-1β in 17KDa active IL-1β peptide, is controlled by caspase-1-dependent pathway, associated with inflammasomes. Other caspase-1 independent mechanisms mediated by proteases, especially as MMPs, have already been described. We evaluated IL-1β activation pathways in neutrophils and monocyte subsets from patients with different clinical forms of Chagas disease after antigen stimulation by multiparameter flow cytometry. Our data demonstrated that Chagas patients with the indeterminate clinical form (IND) showed increased levels of IL-1β post-stimulation as well as increased expression of MMP-2, NLRP3, and CASP1, which are associated with the classical caspase-1-dependent pathway. Conversely, patients with the cardiac clinical form (CARD) showed increased IL-1β after stimulation associated with MMP-9 and alternative caspase-1-independent pathway. We suggest some distinct molecular mechanisms for production of IL-1β in innate immune cells from patients with different clinical forms of Chagas disease. MMP-2 and MMP-9 gelatinases are associated with distinct disease outcomes and IL-1β production.
克氏锥虫心肌病是已知心脏病中主要的纤维性心肌炎。心肌病的发展与细胞外基质（ECM）重塑有关，后者受基质金属蛋白酶（MMPs）和细胞因子调控，尤其是白细胞介素（IL）-1β。31 kDa 无活性前体 proIL-1β向 17 kDa 活性 IL-1β肽的转化受半胱天冬酶-1 依赖性途径控制，与炎性小体有关。其他半胱天冬酶-1 非依赖性机制由蛋白酶介导，特别是 MMPs，已经被描述过。我们通过多参数流式细胞术评估了不同临床形式克氏锥虫病患者中性粒细胞和单核细胞亚群在抗原刺激后 IL-1β激活途径。我们的数据表明，具有不定临床形式（IND）的克氏锥虫病患者在刺激后表现出更高水平的 IL-1β，以及 MMP-2、NLRP3 和 CASP1 的表达增加，这些与经典半胱天冬酶-1 依赖性途径有关。相反，具有心脏临床形式（CARD）的患者在刺激后表现出更高的 IL-1β，与 MMP-9 和替代半胱天冬酶-1 非依赖性途径有关。我们提出了一些不同的分子机制，用于解释不同临床形式克氏锥虫病患者固有免疫细胞中 IL-1β的产生。MMP-2 和 MMP-9 明胶酶与不同的疾病结局和 IL-1β产生有关。
