Radical-Containing Particles Activate Dendritic Cells and Enhance Th17 Inflammation in a Mouse Model of Asthma

Abstract

We identified a previously unrecognized component of airborne particulate matter (PM) formed in combustion and thermal processes, namely, environmentally persistent free radicals (EPFRs). The pulmonary health effects of EPFRs are currently unknown. In the present study, we used a model EPFR-containing pollutant-particle system referred to as MCP230. We evaluated the effects of MCP230 on the phenotype and function of bone marrow-derived dendritic cells (BMDCs) in vitro and lung dendritic cells (DCs) in vivo, and the subsequent T-cell response. We also investigated the adjuvant role of MCP230 on airway inflammation in a mouse model of asthma. MCP230 decreased intracellular reduced glutathione (GSH) and the GSH/oxidized glutathione ratio in BMDCs, and up-regulated the expression of costimulatory molecules CD80 and CD86 on DCs. The maturation of DCs was blocked by inhibiting oxidative stress or the uptake of MCP230. BMDCs exposed to MCP230 increased their antigen-specific T-cell proliferation in vitro. In a model of asthma, exposure to MCP230 exacerbated pulmonary inflammation, which was attributed to the increase of neutrophils and macrophages but not eosinophils. This result correlated with an increase in Th17 cells and cytokines, compared with non-MCP230-treated but ovalbumin (OVA)-challenged mice. The percentage of Th2 cells was comparable between OVA and OVA 1 MCP230 mice. Our data demonstrate that combustion-generated, EPFR-containing PM directly induced the maturation of DCs in an uptake-dependent and oxidative stressdependent manner. Furthermore, EPFR-containing PM induced a Th17-biased phenotype in lung, accompanied by significant pulmonary neutrophilia. Exposure to EPFR-containing PM may constitute an important and unrecognized risk factor in the exacerbation and development of a severe asthma phenotype in humans.

Radical-Containing Ultrafine Particulate Matter Initiates Epithelial-to-Mesenchymal Transitions in Airway Epithelial Cells

“…We also observed uptake in several other cell types, including macrophages and fibroblasts (data not shown). In agreement with our previous studies, we found substantial oxidative stress (glutathione depletion, increased GSSG/GSH ratios, and increased 8-IP levels) in cells exposed to EPFR-containing particles (14,15,24). In this study, oxidative stress was observed at a substantially lower dose (20 mg/cm 2 ).…”

“…The importance of TGF-b in bronchiolar EMT has been shown in recent studies (20,24,52). However, monitoring TGFb in BEAS-2B or neonatal ALI culture supernatants or in vivo at 4 or 7 days after exposure revealed no significant change in TGF-b production before or during EMT (data not shown).…”

“…The total EPFR concentration was 2.5 mM/g PM, and mean diameter was less than 0.2 mm (16). Immediately before use, DCB-230 was suspended in irrigation saline containing 0.02% Tween 80 as previously described (24). In vitro exposures used 20 and 200 mg/cm 2 doses, whereas in vivo inhalation exposures used an environmentally relevant dose of 200 mg/m 3 .…”

Vitamin D Counteracts an IL-23–Dependent IL-17A+IFN-γ+ Response Driven by Urban Particulate Matter

“…The fact that priming DCs with a source of UPM increased the frequency of IL-17A 1 cells concurs with previous studies in mice (31,36) and humans (25,31,37) that identified links between air pollution and IL-17A, albeit in distinct experimental settings. However, in this study, we extend that observation to show that NIST-primed DCs also enhanced the frequency of cells expressing Th17-associated cytokines IL-17F and IL-22, as well as IFN-g, GM-CSF, and granzyme B.…”

Hyperoxidized peroxiredoxins in peripheral blood mononuclear cells of asthma patients is associated with asthma severity

“…Decreased level or function of GSH in antigen-presenting cells, in which the clearing of free radicals is defective, has been shown to increase the numbers of Th2 cells (Kim et al, 2007;Murata et al, 2002;Peterson et al, 1998). Furthermore, oxidative stress has been also reported to modulate the innate and subsequent adaptive immune responses, contributing to the pathogenesis of allergic diseases (Csillag et al, 2010;Wang et al, 2011).…”