Prenatal environmental exposures are increasingly recognized as important risk factors for asthma. Critical exposures include urban air pollution and its component - diesel exhaust. The mechanisms are poorly characterized. This project seeks to address this gap in knowledge. To build a framework for mechanistic studies we have developed a mouse model. In this model, repeated exposure of pregnant mice to diesel exhaust particles (DEP) renders their offspring hypersensitive to the postnatal allergen - ovalbumin (OVA). These offspring develop asthma when subjected to suboptimal OVA sensitization and challenge. In contrast, pups born to unexposed dams do not develop asthma upon suboptimal OVA exposure. Our preliminary data indicate that asthma in this model is mediated by NK cells that produce IL-5, IL-13 and IL-17. Depletion of these cells using specific antibodies prevents asthma. We also show that IL-5/IL-13/IL-17+ NK cells are increased in human asthma. In addition to IL-5, IL-13 and IL-17 production, the pathogenic mouse NK cells are characterized by increased expression of the aryl hydrocarbon receptor (AhR) signature transcripts (AhRR, Cyp1a1 and Cyp1b1). AhR is a transcriptional factor that is known to respond to organic compounds of DEP, namely, polycyclic aromatic hydrocarbons (PAH). AhR is also known to regulate the IL-17 gene transcription. Some reports suggest the positive role of AhR in IL-5 and IL-13 production. Thus, AhR provides a molecular link between maternal exposure to DEP and cytokine production in offspring NK cells. Based on these data, our overarching hypothesis is that in utero exposure to diesel exhaust promotes asthma susceptibility through AhR-dependent priming of NK cells. We propose following specific aims: 1) Examine the importance of NK cells in asthma susceptibility induced via prenatal exposure to DEP; 2) Study the role of the aryl hydrocarbon receptor in NK cell activation and maternal-fetal transmission of asthma risk; 3) Examine the persistence of the pathogenic DEP effect through the life of first and subsequent generations; 4) Examine the relevance of IL- 5/IL-13/IL-17+ NK cells and AhR/AhRR/Cyp1b1+ NK cells in human asthma. To meet these goals we will use NK cell-deficient mice, mice without adaptive immunity and mice with NK cell-specific deletion of AhR. We will also perform transfers of NK cells from prenatally exposed offspring to unexposed mice. To study preservation of asthma susceptibility throughout the offspring life we will use cross-fostering and delayed allergen exposure approaches. To study transgenerational effects of DEP exposure, we will examine asthma susceptibility in F2 and F3 offspring. To determine human relevance we will measure IL-5/IL-13/IL-17+ NK cells and AhR/AhRR/Cyp1b1+ NK cells in young children and adults with asthma. We will correlate NK cell results with amounts of PAH-DNA adducts (a measure of environmental exposure). Using an in vitro culture system we will determine whether DEP can skew non-polarized NK cells from non-allergic non-asthmatic donors into IL-5/IL- 13/IL-17-producing cells. We will then study the role of AhR in this process using a knockdown approach.

Public Health Relevance

Although the role of in utero exposures in development of asthma is increasingly appreciated, the underlying mechanisms remain poorly understood. Our project addresses this gap in knowledge. Our project explores the earliest origins of asthma, thus it has a potential to pave the way for development of asthma prevention regimens.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Noel, Patricia
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National Jewish Health
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