Aryl hydrocarbon receptor targets pathways extrinsic to bone marrow cells to enhance neutrophil recruitment during influenza virus infection

Toxicol Sci. 2008 Mar;102(1):89-99. doi: 10.1093/toxsci/kfm282. Epub 2007 Nov 15.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Cells / virology
  • Bronchoalveolar Lavage Fluid / immunology
  • Bronchoalveolar Lavage Fluid / virology
  • Chimera
  • Disease Models, Animal
  • Environmental Pollutants / toxicity
  • Female
  • Influenza A Virus, H3N2 Subtype*
  • Leukocyte Common Antigens / analysis
  • Lung / drug effects
  • Lung / immunology
  • Lung / metabolism*
  • Lung / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration* / drug effects
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Neutrophils / virology
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism*
  • Orthomyxoviridae Infections / virology
  • Polychlorinated Dibenzodioxins / toxicity
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / deficiency
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Time Factors

Substances

  • Ahr protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Environmental Pollutants
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Leukocyte Common Antigens
  • Ptprc protein, mouse