Abstract
Lung diseases, including asthma, COPD, and other autoimmune lung pathologies are aggravated by exposure to particulate matter (PM) found in air pollution. IL-17 has been shown to exacerbate airway disease in animal models. As PM is known to contain aryl hydrocarbon receptor (AHR) ligands and the AHR has recently been shown to play a role in differentiation of Th17 T cells, the aim of this study was to determine whether exposure to PM could impact Th17 polarization in an AHR-dependent manner. This study used both cell culture techniques and in vivo exposure in mice to examine the response of T cells to PM. Initially experiments were conducted with urban dust particles from a standard reference material, and ultimately repeated with freshly collected samples of diesel exhaust and cigarette smoke. The readout for the assays was increased T cell differentiation as indicated by increased generation of IL-17A in culture, and increased populations of IL-17 producing cells by intracellular flow cytometry. The data illustrate that Th17 polarization was significantly enhanced by addition of urban dust in a dose dependent fashion in cultures of wild-type but not AHR-/- mice. The data further suggest that polycyclic aromatic hydrocarbons played a primary role in this enhancement. There was both an increase of Th17 cell differentiation, and also an increase in the amount of IL-17 secreted by the cells. In summary, this paper identifies a novel mechanism whereby PM can directly act on the AHR in T cells, leading to enhanced Th17 differentiation. Further understanding of the molecular mechanisms responsible for pathologic Th17 differentiation and autoimmunity seen after exposure to pollution will allow direct targeting of proteins involved in AHR activation and function for treatment of PM exposures.
Highlights
Epidemiological studies have established a convincing connection between exposures to atmospheric particulate matter (PM) and increased morbidity and mortality due to airway disease
Because of an interest in the role of immune cells in response to PM, and recent data that PM plays a role in chronic lung rejection driven by IL-17 [5,6], the effects of SRM1649b were tested in murine mixed leukocyte cultures (MLC)
In co-cultures of B6 splenocytes and Balb/c dendritic cells (DC), IL-17A levels increased in the supernatant by ELISA in MLC containing FICZ while the addition of 40 μg/ml SRM1649b increased IL-17A 8-fold higher still (Figure 1B)
Summary
Epidemiological studies have established a convincing connection between exposures to atmospheric particulate matter (PM) and increased morbidity and mortality due to airway disease. Exposure to air pollutants has been correlated with increases in the incidence and severity of asthma [1,2], chronic obstructive pulmonary disease (COPD) [3], respiratory infection [4] and even the rejection of lung allografts [5,6]. IL-17A has been implicated as an important component of airway diseases including asthma [11] and COPD [12] as well as the rejection of lung transplants [13,14]. Exposure to PM in vivo has been shown to upregulate IL-17 expression in the lung [15,16] or the gut [17]
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