Novel Cellular Targets of AhR Underlie Alterations in Neutrophilic Inflammation and Inducible Nitric Oxide Synthase Expression during Influenza Virus Infection

Abstract

The underlying reasons for variable clinical outcomes from respiratory viral infections remain uncertain. Several studies suggest that environmental factors contribute to this variation, but limited knowledge of cellular and molecular targets of these agents hampers our ability to quantify or modify their contribution to disease and improve public health. The aryl hydrocarbon receptor (AhR) is an environment sensing transcription factor that binds many anthropogenic and natural chemicals. The immunomodulatory properties of AhR ligands are best characterized with extensive studies of changes in CD4+ T cell responses. Yet, AhR modulates other aspects of immune function. We previously showed that during influenza virus infection, AhR activation modulates neutrophil accumulation in the lung, and this contributes to increased mortality in mice. Enhanced levels of inducible nitric oxide synthase (iNOS) in infected lungs are observed during the same timeframe as AhR-mediated increased pulmonary neutrophilia. In this study, we evaluated whether these two consequences of AhR activation are causally linked. Reciprocal inhibition of AhR-mediated elevations in iNOS and pulmonary neutrophilia reveal that, although they are contemporaneous, they are not causally related. We show using Cre/loxP technology that elevated iNOS levels and neutrophil number in the infected lung result from separate, AhR-dependent signaling in endothelial and respiratory epithelial cells, respectively. Studies using mutant mice further reveal that AhR-mediated alterations in these innate responses to infection require a functional nuclear localization signal and DNA binding domain. Thus, gene targets of AhR in non-hematopoietic cells are important new considerations for understanding AhR-mediated changes in innate anti-viral immunity.

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

“…Additionally, it is associated with antiviral immunity (10) and is a negative regulator of inflammatory cytokines in response to Leishmania major experimental infection (11). Taken together, the results of these studies strongly suggest that AhR function during immune responses to infections is complex and likely pathogen specific.…”

Benzo[a]pyrene-induced nitric oxide production acts as a survival signal targeting mitochondrial membrane potential

“…With respect to AhR, a recent study also indicated a role for this receptor in the iNOS induction detected in lungs infected by influenza virus, likely through a paracrine mechanism; indeed, whereas AhR was activated in endothelial cells, iNOS induction was observed both in epithelial cells and macrophages, therefore suggesting the involvement of an iNOS regulator released by endothelial cells (Wheeler et al, 2013). In our experiments, as only one cell type exists in F258 cell line, such a paracrine mechanism would be unlikely to occur.…”

Local Generation of Kynurenines Mediates Inhibition of Neutrophil Chemotaxis by Uropathogenic Escherichia coli

“…For example, pretreatment of mice with TCDD suppressed neutrophil recruitment to the murine lung following intranasal inoculation with Streptococcus pneumoniae (46). However, in potential contrast, TCDD activation of AHR-dependent signaling in respiratory epithelial cells appeared to increase neutrophil recruitment to the lungs of influenza virusinfected mice, while neutrophil numbers were not increased systemically or in hematopoietic tissue (7,47). These apparently incompatible results may arise from effects of dosage, host and microbial contexts, relative contributions of multiple cell types to the phenotypic results, and the presence of additional AHR ligands in the respective model systems.…”