Suppression of the NF-kB Pathway by Diesel Exhaust Particles Impairs Human Antimycobacterial Immunity

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-kB 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-g, TNF-a, IL-1b, 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-kB (e. 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. A ir pollution and tuberculosis (TB) each contribute significantly to global burden of disease. The World Health Organization estimates that air pollution, which is linked to a variety of illnesses including cardiopulmonary diseases and cancer, causes ∼2 million premature deaths worldwide per year (1). According to the World Health Organization's 2009 Global Health Risk report (2), indoor air pollution (from biomass fuel and coal combustion) and urban outdoor air pollution rank 10th and 14th, respectively, among 19 leading risk factors for mortality in low-and middle-income countries. Exposure to ambient-air fine particulate matter ,2.5 mm in aerodynamic diameter (PM 2.5) is estimated to cause ∼1% of mortality from acute respiratory infections in children .5 y worldwide (3). TB was estimated to afflict ∼10 million people and cause 2 million deaths in 2010 alone (4). Epidemiologic associations have been established between the incidence of TB and, respectively, cigarette smoking (5–11), occupational exposure to aerosolized …