Involvement of TLR2 and TLR4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter

Abstract

Induction of proinflammatory mediators by alveolar macrophages exposed to ambient air particulate matter has been suggested to be a key factor in the pathogenesis of inflammatory and allergic diseases in the lungs. However, receptors and mechanisms underlying these responses have not been fully elucidated. In this study, we examined whether TLR2, TLR4, and the key adaptor protein, MyD88, mediate the expression of proinflammatory cytokines and chemokines by mouse peritoneal macrophages exposed to fine and coarse PM. TLR2 deficiency blunted macrophage TNF-alpha and IL-6 expression in response to fine (PM2.5), while not affecting cytokine-inducing ability of coarse NIST Standard Reference Material (SRM 1648) particles. In contrast, TLR4(-/-) macrophages showed inhibited cytokine expression upon stimulation with NIST SRM 1648 but exhibited normal responses to PM2.5. Preincubation with polymyxin B markedly suppressed the capacity of NIST SRM 1648 to elicit TNF-alpha and IL-6, indicating endotoxin as a principal inducer of cytokine responses. Overexpression of TLR2 in TLR2/4-deficient human embryonic kidney 293 cells imparted PM2.5 sensitivity, as judged by IL-8 gene expression, whereas NIST SRM 1648, but not PM2.5 elicited IL-8 expression in 293/TLR4/MD-2 transfectants. Engagement of TLR4 by NIST SRM 1648 induced MyD88-independent expression of the chemokine RANTES, while TLR2-reactive NIST IRM PM2.5 failed to up-regulate this response. Consistent with the shared use of MyD88 by TLR2 and TLR4, cytokine responses of MyD88(-/-) macrophages to both types of air PM were significantly reduced. These data indicate differential utilization of TLR2 and TLR4 but shared use of MyD88 by fine and coarse air pollution particles.

Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease

“…TLR4 point mutant mice, compared with wild-type mice, show decreased lung inflammation and neutrophil influx in BAL upon exposure to diesel exhaust particles (Inoue et al, 2006). TLR2 and TLR4 are also involved in the immune response against fine and coarse air-pollution particles (Shoenfelt et al, 2009). Inhaled ozone, another risk factor for airway diseases, alters the distribution of TLR4 on alveolar macrophages and increases the functional response of alveolar macrophages to endotoxin (Hollingsworth et al, 2007).…”

Diabetes and Metabolic Syndrome

“…In contrast, exposure to PM 10 that had high levels of endotoxin activates macrophage in a TLR4-dependent mechanism. However, fi ne and coarse air pollution particles-elicited infl ammatory response shared the same downstream signaling pathways, MyD88, despite differential utilization of TLR2 and TLR4 (Sun et al 2010 ;Shoenfelt et al 2009 ).…”

Temporal And Spatial Patterns Of Ambient Endotoxin Concentrations In Fresno, California

“…Moreover, high endotoxin concentrations (> 5 EU/m 3 ) were most frequently observed on days when the concentrations of PM 2.5 were below the current daily national standard of 35 µg/m 3 ( Figure 2B). Given the proinflammatory properties of endotoxins (Monn and Becker 1999;Shoenfelt et al 2009;Soukup and Becker 2001), ambient endotoxin concentrations likely play a role in respiratory outcomes associated with PM. In our study area, endotoxin concentrations are highest during dry seasons.…”