Dioxin-induced deregulation of neutrophil recruitment to the lungs of mice infected with influenza virus

The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) has the highest binding affinity for an orphan transcriptional regulator called the aryl hydrocarbon receptor (AhR). Immune modulation is one of the most sensitive adverse health effects observed in rodents treated with the AhR ligand TCDD, and numerous studies have shown that exposure to TCDD severely suppresses adaptive immunity. In contrast, a limited number of studies have examined the effects of TCDD on the inflammatory response. Studies conducted by us and others have shown that exposure to TCDD enhances inflammation, characterized by increased number of neutrophils at the site of antigen challenge. However, the mechanism underlying this exacerbated neutrophilia remains to be elucidated.; The overall goal of this dissertation was to determine the mechanism that underlies the enhanced number of neutrophils in the lungs of TCDD-treated, influenza virus-infected mice. In these studies, we demonstrated that AhR activation directly mediates the excess number of neutrophils in lungs of TCDD-exposed, infected mice. Furthermore, we determined that in vivo depletion of neutrophils in TCDD-treated mice significantly improved survival following infection with influenza virus. However, our data indicate that exposure to TCDD did not elevate levels of soluble neutrophil-chemoattractants in the lung, up-regulate expression of adhesion molecules on pulmonary neutrophils, or delay pulmonary neutrophil apoptosis in infected mice. Furthermore, treatment with TCDD did not increase pulmonary vascular permeability, leading to leakage of neutrophils from the blood stream to the lungs.; Additionally, we have shown that exposure to TCDD did not systemically enhance the number of neutrophils. In the absence of a direct effect of TCDD on pulmonary neutrophils and given our finding that the excess neutrophilia was restricted to the site of antigen challenge (i.e., the lung), we determined whether AhR-mediated events within or external to the immune system underlie the exacerbated neutrophilia. We found that TCDD-treated, infected CD45.2AhR -/-→CD45.1AhR+/+ bone marrow chimeric mice had an excess of pulmonary neutrophils, indicating that AhR-driven events external to the immune system mediate the enhanced neutrophilia. These novel findings indicate that AhR-driven events external to the immune system underlie deregulated neutrophil recruitment to the lungs of mice treated with TCDD.