Department of Environmental and Occupational Health, University of Medicine and Dentistry of New Jersey-School of Public Health, Piscataway, NJ 08854, USA.
J Immunol. 2012 Mar 15;188(6):2778-93. doi: 10.4049/jimmunol.1101380. Epub 2012 Feb 15.
Epidemiological studies suggest that chronic exposure to air pollution increases susceptibility to respiratory infections, including tuberculosis in humans. A possible link between particulate air pollutant exposure and antimycobacterial immunity has not been explored in human primary immune cells. We hypothesized that exposure to diesel exhaust particles (DEP), a major component of urban fine particulate matter, suppresses antimycobacterial human immune effector cell functions by modulating TLR-signaling pathways and NF-κB activation. We show that DEP and H37Ra, an avirulent laboratory strain of Mycobacterium tuberculosis, were both taken up by the same peripheral human blood monocytes. To examine the effects of DEP on M. tuberculosis-induced production of cytokines, PBMC were stimulated with DEP and M. tuberculosis or purified protein derivative. The production of M. tuberculosis and purified protein derivative-induced IFN-γ, TNF-α, IL-1β, and IL-6 was reduced in a DEP dose-dependent manner. In contrast, the production of anti-inflammatory IL-10 remained unchanged. Furthermore, DEP stimulation prior to M. tuberculosis infection altered the expression of TLR3, -4, -7, and -10 mRNAs and of a subset of M. tuberculosis-induced host genes including inhibition of expression of many NF-κB (e.g., CSF3, IFNG, IFNA, IFNB, IL1A, IL6, and NFKBIA) and IFN regulatory factor (e.g., IFNG, IFNA1, IFNB1, and CXCL10) pathway target genes. We propose that DEP downregulate M. tuberculosis-induced host gene expression via MyD88-dependent (IL6, IL1A, and PTGS2) as well as MyD88-independent (IFNA, IFNB) pathways. Prestimulation of PBMC with DEP suppressed the expression of proinflammatory mediators upon M. tuberculosis infection, inducing a hyporesponsive cellular state. Therefore, DEP alters crucial components of antimycobacterial host immune responses, providing a possible mechanism by which air pollutants alter antimicrobial immunity.
流行病学研究表明，慢性暴露于空气污染会增加人类对呼吸道感染（包括结核病）的易感性。在人类原代免疫细胞中，尚未探索过颗粒状空气污染物暴露与抗分枝杆菌免疫之间的可能联系。我们假设，暴露于柴油废气颗粒（DEP）——城市细颗粒物的主要成分——通过调节 TLR 信号通路和 NF-κB 激活来抑制抗分枝杆菌的人类免疫效应细胞功能。我们表明，DEP 和 H37Ra（结核分枝杆菌的无毒实验室株）均被外周血单核细胞摄取。为了研究 DEP 对结核分枝杆菌诱导的细胞因子产生的影响，用 DEP 和结核分枝杆菌或纯化蛋白衍生物刺激 PBMC。DEP 剂量依赖性地降低了结核分枝杆菌和纯化蛋白衍生物诱导的 IFN-γ、TNF-α、IL-1β 和 IL-6 的产生。相比之下，抗炎性 IL-10 的产生保持不变。此外，在结核分枝杆菌感染之前用 DEP 刺激改变了 TLR3、-4、-7 和 -10 mRNA 的表达以及结核分枝杆菌诱导的宿主基因的子集的表达，包括许多 NF-κB（例如 CSF3、IFNG、IFNA、IFNB、IL1A、IL6 和 NFKBIA）和 IFN 调节因子（例如 IFNG、IFNA1、IFNB1 和 CXCL10）途径靶基因的表达抑制。我们提出，DEP 通过 MyD88 依赖性（IL6、IL1A 和 PTGS2）以及 MyD88 非依赖性（IFNA、IFNB）途径下调结核分枝杆菌诱导的宿主基因表达。用 DEP 预刺激 PBMC 可抑制结核分枝杆菌感染后促炎介质的表达，诱导低反应性细胞状态。因此，DEP 改变了抗分枝杆菌宿主免疫反应的关键组成部分，为空气污染物改变抗菌免疫提供了一种可能的机制。
