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

Urban particulate matter (UPM) air pollution and vitamin D deficiency are detrimentally associated with respiratory health. This is hypothesized to be due in part to regulation of IL-17A, which UPM is reported to promote. Here, we used a myeloid dendritic cell (DC)-memory CD4+ T cell co-culture system to characterize UPM-driven IL-17A+ cells, investigate the mechanism by which UPM-primed DCs promote this phenotype, and address evidence for cross-regulation by vitamin D. CD1c+ myeloid DCs were cultured overnight with or without a reference source of UPM and/or active vitamin D (1,25[OH]2D3) before they were co-cultured with autologous memory CD4+ T cells. Supernatants were harvested for cytokine analysis on Day 5 of co-culture, and intracellular cytokine staining was performed on Day 7. UPM-primed DCs increased the proportion of memory CD4+ T cells expressing the T helper 17 cell (Th17)-associated cytokines IL-17A, IL-17F, and IL-22, as well as IFN-γ, granulocyte-macrophage colony-stimulating factor, and granzyme B. Notably, a large proportion of the UPM-driven IL-17A+ cells co-expressed these cytokines, but not IL-10, indicative of a proinflammatory Th17 profile. UPM-treated DCs expressed elevated levels of il23 mRNA and increased secretion of IL-23p40. Neutralization of IL-23 in culture reduced the frequency of IL-17A+IFN-γ+ cells without affecting cell proliferation. 1,25(OH)2D3 counteracted the UPM-driven DC maturation and inhibited the frequency of IL-17A+IFN-γ+ cells, most prominently when DCs were co-treated with the corticosteroid dexamethasone, while maintaining antiinflammatory IL-10 synthesis. These data indicate that UPM might promote an inflammatory milieu in part by inducing an IL-23-driven proinflammatory Th17 response. Restoring vitamin D sufficiency may counteract these UPM-driven effects without obliterating important homeostatic immune functions.

WITHDRAWN: Allergic mechanisms of asthma are enhanced during the summer with oxidant PM10 components.

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Air pollution and its effects on the immune system.

A well-functioning immune system is vital for a healthy body. Inadequate and excessive immune responses underlie diverse pathologies such as serious infections, metastatic malignancies and auto-immune conditions. Therefore, understanding the effects of ambient pollutants on the immune system is vital to understanding how pollution causes disease, and how that pathology could be abrogated. The immune system itself consists of multiple types of immune cell that act together to generate (or fail to generate) immune responses and in this article we review evidence of how air pollutants can affect different immune cell types such as particle-clearing macrophages, inflammatory neutrophils, dendritic cells that orchestrate adaptive immune responses and lymphocytes that enact those responses. Common themes that emerge are of the capacity of air pollutants to stimulate pro-inflammatory immune responses across multiple classes of immune cell. Air pollution can enhance T helper lymphocyte type 2 (Th2) and T helper lymphocyte type 17 (Th17) adaptive immune responses, as seen in allergy and asthma, and dysregulate anti-viral immune responses. The clinical effects of air pollution, in particular the known association between elevated ambient pollution and exacerbations of asthma and chronic obstructive pulmonary disease (COPD), are consistent with these identified immunological mechanisms. Further to this, as inhaled air pollution deposits primarily on the respiratory mucosa this review focuses on mechanisms of respiratory disease. However, as discussed in the article, air pollution also affects the wider immune system for example in the neonate and gastrointestinal tract. Whilst the many identified actions of air pollution on the immune system are notably diverse, immunological research does suggest potential strategies to ameliorate such effects, for example with vitamin D supplementation. An in-depth understanding of the immunological effects of ambient pollutants should hopefully yield new ideas on how to reduce the adverse health effects of air pollution.

Effects of vitamin D on inflammatory and oxidative stress responses of human bronchial epithelial cells exposed to particulate matter.

BACKGROUND: Particulate matter (PM) pollutant exposure, which induces oxidative stress and inflammation, and vitamin D insufficiency, which compromises immune regulation, are detrimental in asthma. OBJECTIVES: Mechanistic cell culture experiments were undertaken to ascertain whether vitamin D abrogates PM-induced inflammatory responses of human bronchial epithelial cells (HBECs) through enhancement of antioxidant pathways. METHODS: Transcriptome analysis, PCR and ELISA were undertaken to delineate markers of inflammation and oxidative stress; with comparison of expression in primary HBECs from healthy and asthmatic donors cultured with reference urban PM in the presence/absence of vitamin D. RESULTS: Transcriptome analysis identified over 500 genes significantly perturbed by PM-stimulation, including multiple pro-inflammatory cytokines. Vitamin D altered expression of a subset of these PM-induced genes, including suppressing IL6. Addition of vitamin D suppressed PM-stimulated IL-6 production, although to significantly greater extent in healthy versus asthmatic donor cultures. Vitamin D also differentially affected PM-stimulated GM-CSF, with suppression in healthy HBECs and enhancement in asthmatic cultures. Vitamin D increased HBEC expression of the antioxidant pathway gene G6PD, increased the ratio of reduced to oxidised glutathione, and in PM-stimulated cultures decreased the formation of 8-isoprostane. Pre-treatment with vitamin D decreased CXCL8 and further decreased IL-6 production in PM-stimulated cultures, an effect abrogated by inhibition of G6PD with DHEA, supporting a role for this pathway in the anti-inflammatory actions of vitamin D. CONCLUSIONS: In a study using HBECs from 18 donors, vitamin D enhanced HBEC antioxidant responses and modulated the immune response to PM, suggesting that vitamin D may protect the airways from pathological pollution-induced inflammation.