ToxSci Advance Access originally published online on November 15, 2007
Toxicological Sciences 2008 102(1):89-99; doi:10.1093/toxsci/kfm282
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Aryl Hydrocarbon Receptor Targets Pathways Extrinsic to Bone Marrow Cells to Enhance Neutrophil Recruitment during Influenza Virus Infection
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* Department of Pharmaceutical Sciences and Pharmacology/Toxicology Graduate Program, College of Pharmacy
Department of Veterinary Clinical Sciences, College of Veterinary Medicine
Department of Molecular Biosciences Graduate Program, Washington State University, Pullman, Washington 99164
2 To whom correspondence should be addressed at Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, 575 Elmwood Ave, Box 850, Rochester, NY 14642. Fax: (585) 276-0239. E-mail: paige_lawrence{at}urmc.rochester.edu.
Received August 31, 2007; accepted November 9, 2007
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Abstract |
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There is growing evidence that neutrophils influence host resistance during influenza virus infection; however, factors that regulate neutrophil migration to the lung during viral infection are unclear. Activation of the aryl hydrocarbon receptor (AhR) by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) results in an increased number of neutrophils in the lung after influenza virus infection. The mechanism of AhR-mediated neutrophilia does not involve elevated levels of soluble neutrophil chemoattractants, upregulated adhesion molecules on pulmonary neutrophils, delayed neutrophil apoptosis, or increased vascular damage. In this study, we determined whether AhR activation increases neutrophil numbers systemically or only in the infected lung, and whether AhR-regulated events within the hematopoietic system underlie the dioxin-induced increase in pulmonary neutrophils observed during influenza virus infection. We report here that AhR activation does not increase neutrophil numbers systemically or increase neutrophil production in hematopoietic tissue, suggesting that the elevated number of neutrophils is restricted to the site of antigen challenge. The generation of CD45.2AhR–/– 
CD45.1AhR+/+ bone marrow chimeric mice demonstrates that even when hematopoietic cells lack the AhR, TCDD treatment still results in twice as many pulmonary neutrophils compared with control-treated, infected CD45.2AhR–/– CD45.1AhR+/+ chimeric mice. This finding reveals that AhR-mediated events extrinsic to bone marrow–derived cells affect the directional migration of neutrophils to the infected lung. These results suggest that the lung contains important and heretofore overlooked targets of AhR regulation, unveiling a novel mechanism for controlling neutrophil recruitment to the infected lung.
Key Words: pulmonary inflammation; respiratory infection; Per-Arnt-Sim proteins; environmental pollutants; dioxin receptor.
1 Present address: Department of Microbiology, Immunology & Pathology, Colorado State University, Ft. Collins, CO.
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