Abstract
BackgroundThe exposure to pollutants such as diesel exhaust particles (DEP) is associated with an increased incidence of respiratory diseases. However, the mechanisms by which DEP have an effect on human health are not completely understood. In addition to their action on macrophages and airway epithelial cells, DEP also modulate the functions of dendritic cells (DC). These professional antigen-presenting cells are able to discriminate unmodified self from non-self thanks to pattern recognition receptors such as the Toll like Receptors (TLR) and Scavenger Receptors (SR). SR were originally identified by their ability to bind and internalize modified lipoproteins and microorganisms but also particles and TLR agonists. In this study, we assessed the implication of SR in the effects of DEP associated or not with TLR agonists on monocyte-derived DC (MDDC). For this, we studied the regulation of CD36, CXCL16, LOX-1, SR-A1 and SR-B1 expression on MDDC treated with DEP associated or not with TLR2, 3 and 4 ligands. Then, the capacity of SR ligands (dextran sulfate and maleylated-ovalbumin) to block the effects of DEP on the function of lipopolysaccharide (LPS)-activated DC has been evaluated.ResultsOur data demonstrate that TLR2 agonists mainly augmented CXCL16, LOX-1 and SR-B1 expression whereas DEP alone had only a weak effect. Interestingly, DEP modulated the action of TLR2 and TLR4 ligands on the expression of LOX-1 and SR-B1. Pretreatment with the SR ligand maleylated-ovalbumin but not dextran sulfate inhibited the endocytosis of DEP by MDDC. Moreover, this SR ligand blocked the effect by DEP at low dose (1 μg/ml) on MDDC phenotype (a decrease of CD86 and HLA-DR expression) and on the secretion of CXCL10, IL-12 and TNF-α. In contrast, the decrease of IL-12 and CXCL10 secretion and the generation of oxygen metabolite induced by DEP at 10 μg/ml was not affected by SR ligandsConclusionOur results show for the first time that the modulation of DC functions by DEP implicates SR. TLR agonists upregulated SR expression in contrast to DEP. Interfering with the expression and/or the function of SR might be one way to limit the impact of DEP on lung immune response.
Highlights
The exposure to pollutants such as diesel exhaust particles (DEP) is associated with an increased incidence of respiratory diseases
Modulation of Messenger Ribonucleic Acid (mRNA) expression of the Scavenger Receptors (SR) CD36, CXCL16, LOX-1, SR-A1 and SR-B1/CLA-1 by DEP and Toll like Receptors (TLR) ligands We first determined whether DEP alone or in costimulation with TLR2 (Pam3CSK4 (10 μg/ml)), -3 (Polyinosinic-polycytidylic acid (poly(I:C))) (10 μg/ml), -4
The TLR2 ligand significantly increased the mRNA level of CXCL16 (p < 0.001) and SR-B1 (p < 0.001), after 1 h stimulation, and LOX-1 after 1 and 3 h stimulation (Fig 1A and 1B) (p < 0.05)
Summary
The exposure to pollutants such as diesel exhaust particles (DEP) is associated with an increased incidence of respiratory diseases. DC has been shown as playing a key role in the control of the lung immune response These effects induced by DEP are probably responsible for its adjuvant activity that promotes pro-allergic sensitization to common environmental allergens [5], exacerbation of existing airway diseases [6,7], and increased susceptibility to respiratory virus infections like influenza [8] or RSV infections [9]. Regarding the modulation of DC functions, DEP do not induce their maturation but rather slightly modulate the response to potent maturation agents such as lipopolysaccharide (LPS), a ligand of Toll-Like Receptor (TLR)4 [10,11] This effect involves the generation of reactive oxygen species (ROS) and the inhibition of NF-κB activation [12]. The early mechanisms by which DEP affect DC functions are not completely understood
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