Dissertation/Thesis Abstract

Sustained Aryl Hydrocarbon Receptor Activation and its Role in Neutrophil Recruitment and Inducible Nitric Oxide Synthase Expression in the Lung During Influenza A Virus Infection
by Head, Jennifer, Ph.D., University of Rochester, 2011, 146; 3498244
Abstract (Summary)

The aryl hydrocarbon receptor (AhR) is a known modulator of immune responses. In a mouse model of influenza virus infection, AhR activation with 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) exacerbates neutrophil recruitment to the lung, causing increased mortality. Given that elevated pulmonary neutrophilia has been linked to worsened outcomes in a variety of disease models, determining the underlying mechanisms responsible for excessive neutrophil recruitment could have significant therapeutic potential. Known mechanisms of neutrophil recruitment are not affected by TCDD, suggesting a novel pathway could exist, which is sensitive to AhR activation. Interestingly, increased expression of inducible nitric oxide synthase (iNOS) in the lung during infection is also observed following AhR activation with TCDD. We hypothesize that AhR-mediated increases in iNOS levels are responsible for the enhanced recruitment of neutrophils to the infected lung. However, using several approaches to inhibit iNOS and deplete neutrophils, we show that increases in neutrophilia are not dependent on iNOS expression. Further, utilizing Cre recombinase-mediated AhR excision, we demonstrate that while AhR activation within the endothelium regulates iNOS expression, elevations in neutrophil recruitment are mediated by AhR activation within the respiratory epithelium. These results demonstrate that AhR activation increases neutrophil recruitment and iNOS levels through independent mechanisms in distinct cellular targets. This new information provides opportunities for understanding how the AhR regulates the balance between excessive and appropriate inflammation following viral infection.

To further probe the AhR’s impact on the immune response to infection, we chose the non-anthropogenic high-affinity AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ). Whereas TCDD has a long half-life (8-10 days) in mice, FICZ’s half-life is only several hours due to its rapid metabolism. Given this disparity, we hypothesize that the duration of AhR activation is an important parameter in AhR-mediated modulation of the immune response to influenza virus. We show that transient AhR activation by FICZ does not affect innate or adaptive immune responses known to be affected by TCDD. Further, prolonged FICZ-mediated AhR activation also has no impact on these immune responses. Our data indicate that in addition to duration, other aspects of AhR activation are critical factors in immune modulation.

Indexing (document details)
Advisor: Lawrence, B. Paige
Commitee: Brookes, Paul, Gasiewicz, Thomas, Kim, Minsoo, Rahman, Arshad
School: University of Rochester
Department: School of Medicine and Dentistry
School Location: United States -- New York
Source: DAI-B 73/07(E), Dissertation Abstracts International
Subjects: Toxicology, Surgery, Immunology
Keywords: Aryl hydrocarbon receptor, Influenza A virus, Lung, Neutrophils, Nitric oxide synthase
Publication Number: 3498244
ISBN: 9781267206350
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