Synergistic Costimulatory Effect of Chlamydia pneumoniae with Carbon Nanoparticles on NLRP3 Inflammasome-Mediated Interleukin-1β Secretion in Macrophages

Abstract

The obligate intracellular bacterium Chlamydia pneumoniae is not only a causative agent of community-acquired pneumonia but is also associated with a more serious chronic disease, asthma, which might be exacerbated by air pollution containing carbon nanoparticles. Although a detailed mechanism of exacerbation remains unknown, the proinflammatory cytokine interleukin-1␤ (IL-1␤) is a critical player in the pathogenesis of asthma. C. pneumoniae induces IL-1␤ in macrophages via NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activation and Toll-like receptor 2/4 (TLR2/4) stimulation. Carbon nanoparticles, such as carbon nanotubes (CNTs), can also evoke the NLRP3 inflammasome to trigger IL-1␤ secretion from lipopolysaccharide-primed macrophages. This study assessed whether costimulation of C. pneumoniae with CNTs synergistically enhanced IL-1␤ secretion from macrophages, and determined the molecular mechanism involved. Enhanced IL-1␤ secretion from C. pneumoniae-infected macrophages by CNTs was dose and time dependent. Transmission electron microscopy revealed that C. pneumoniae and CNTs were engulfed concurrently by macrophages. Inhibitors of actin polymerization or caspase-1, a component of the inflammasome, significantly blocked IL-1␤ secretion. Gene silencing using small interfering RNA (siRNA) targeting the NLRP3 gene also abolished IL-1␤ secretion. Other inhibitors (K ؉ efflux inhibitor, cathepsin B inhibitor, and reactive oxygen species-generating inhibitor) also blocked IL-1␤ secretion. Taken together, these findings demonstrated that CNTs synergistically enhanced IL-1␤ secretion from C. pneumoniae-infected macrophages via the NLRP3 inflammasome and caspase-1 activation, providing novel insight into our understanding of how C. pneumoniae infection can exacerbate asthma. Chlamydia pneumoniae is an obligate intracellular bacterium and a causative agent of respiratory tract infections, including community-acquired pneumonia (1, 2). The seroprevalence rates of C. pneumoniae infection, which start to rise relatively early in childhood, are increased by 50% at 20 years of age and subsequently reach 70 to 80% by 60 to 70 years of age (3, 4), suggesting most individuals will have had some exposure to the bacterium in their lifetime. Therefore, C. pneumoniae is likely a ubiquitous pathogen in individuals worldwide (4). The symptoms of pulmonary infection vary considerably according to age from asymptomatic or mild illness to serious pneumonia, especially in pediatric infection (1-3). Regarding this, several studies indicate that bacterial infection might exacerbate pulmonary inflammation and thus is associated with a more serious chronic disease, asthma (3). The proinflammatory cytokine interleukin-1␤ (IL-1␤), which is induced by C. pneumoniae (5-8), is thought to play a critical role in the development of chronic inflammatory disease, although detailed mechanisms remain unclear. Air pollution containing carbon nanoparticles, environmental air contaminants that might be easily inhaled with C. pneu...

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