Insight into AhR-mediated increases in neutrophilia during infection: iNOS as a potentially new AhR target gene (37.26)

Abstract

There are many known factors that can affect immune responses to respiratory viral infections such as influenza A virus. Indeed, recent epidemiological studies indicate that in addition to host genetics, age and pathogen sub-types, a variety of environmental factors also impact the immune response to infections. Many of these environmental factors, including diesel exhaust and cigarette smoke, contain ligands for the aryl hydrocarbon receptor (AhR), an environment-sensing transcription factor shown to affect multiple facets of the immune system. Our laboratory has shown that activation of the AhR by the persistent environmental contaminant dioxin exacerbates neutrophil recruitment and increases the expression of inducible nitric oxide synthase (iNOS) in the lungs of influenza virus-infected mice. We show that depleting neutrophils during viral infection does not abrogate AhR-mediated increases in iNOS expression, demonstrating that neutrophil recruitment is downstream of elevated iNOS. We also show that AhR activation in iNOS-deficient mice infected with influenza virus does not affect neutrophil recruitment to the lung. Thus, these findings suggest that these AhR-mediated events are linked, and that increased iNOS expression could be a novel mechanism regulating neutrophil migration the infected lung. Additionally these studies implicate iNOS as a novel AhR target gene and provide new insights into the mechanisms underlying leukocyte recruitment during viral infections.