Hernández-Jiménez Enrique, Gutierrez-Fernández María, Cubillos-Zapata Carolina, Otero-Ortega Laura, Rodríguez-Frutos Berta, Toledano Víctor, Martínez-Sánchez Patricia, Fuentes Blanca, Varela-Serrano Aníbal, Avendaño-Ortiz José, Blázquez Alberto, Mangas-Guijarro María Ángeles, Díez-Tejedor Exuperio, López-Collazo Eduardo
Tumor Immunology Laboratory, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.
Innate Immunity Group, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.
J Immunol. 2017 Mar 1;198(5):2038-2046. doi: 10.4049/jimmunol.1601594. Epub 2017 Jan 23.
Patients with acute ischemic stroke (AIS) suffer from infections associated with mortality. The relevance of the innate immune system, and monocytes in particular, has emerged as an important factor in the evolution of these infections. The study enrolled 14 patients with AIS, without previous treatment, and 10 healthy controls. In the present study, we show that monocytes from patients with AIS exhibit a refractory state or endotoxin tolerance. The patients were unable to orchestrate an inflammatory response against LPS and expressed three factors reported to control the evolution of human monocytes into a refractory state: IL-1R-associated kinase-M, NFkB2/p100, and hypoxia-inducible factor-1α. The levels of circulating mitochondrial DNA (mtDNA) in patients with AIS correlated with impaired inflammatory response of isolated monocytes. Interestingly, the patients could be classified into two groups: those who were infected and those who were not, according to circulating mtDNA levels. This finding was validated in an independent cohort of 23 patients with AIS. Additionally, monocytes from healthy controls, cultured in the presence of both sera from patients and mtDNA, reproduced a refractory state after endotoxin challenge. This effect was negated by either a TLR9 antagonist or DNase treatment. The present data further extend our understanding of endotoxin tolerance implications in AIS. A putative role of mtDNA as a new biomarker of stroke-associated infections, and thus a clinical target for preventing poststroke infection, has also been identified.
急性缺血性卒中（AIS）患者会遭受与死亡率相关的感染。固有免疫系统，尤其是单核细胞的相关性，已成为这些感染发展过程中的一个重要因素。该研究纳入了14例未经前期治疗的AIS患者和10名健康对照者。在本研究中，我们发现AIS患者的单核细胞呈现出一种难治性状态或内毒素耐受性。这些患者无法对脂多糖（LPS）协调炎症反应，并且表达了三种据报道可控制人类单核细胞发展为难治性状态的因子：白细胞介素-1受体相关激酶-M（IL-1R-associated kinase-M）、核因子κB2/p100（NFkB2/p100）和缺氧诱导因子-1α（hypoxia-inducible factor-1α）。AIS患者循环线粒体DNA（mtDNA）水平与分离出的单核细胞炎症反应受损相关。有趣的是，根据循环mtDNA水平，患者可分为两组：感染组和未感染组。这一发现在一个由23例AIS患者组成的独立队列中得到了验证。此外，在来自患者的血清和mtDNA存在的情况下培养的健康对照者的单核细胞，在内毒素刺激后再现了难治性状态。这种效应可被Toll样受体9（TLR9）拮抗剂或脱氧核糖核酸酶（DNase）处理所消除。目前的数据进一步扩展了我们对AIS中内毒素耐受性影响的理解。还确定了mtDNA作为卒中相关感染新生物标志物的假定作用，因此也是预防卒中后感染的临床靶点。
