Aryl Hydrocarbon Receptor Activation during Influenza Virus Infection Unveils a Novel Pathway of IFN-γ Production by Phagocytic Cells

Abstract

The contribution of environmental factors is important as we consider reasons that underlie differential susceptibility to influenza virus. Aryl hydrocarbon receptor (AhR) activation by the pollutant dioxin during influenza virus infection decreases survival, which correlates with a 4-fold increase in pulmonary IFN-γ levels. We report here that the majority of IFN-γ-producing cells in the lung are neutrophils and macrophages not lymphocytes, and elevated IFN-γ is associated with increased pulmonary inducible NO synthase (iNOS) levels. Moreover, we show that even in the absence of dioxin, infection with influenza virus elicits IFN-γ production by B cells, γδ T cells, CD11c+ cells, macrophages and neutrophils, as well as CD3+ and NK1.1+ cells in the lung. Bone marrow chimeric mice reveal that AhR-mediated events external to hemopoietic cells direct dioxin-enhanced IFN-γ production. We also show that AhR-mediated increases in IFN-γ are dependent upon iNOS, but elevated iNOS in lung epithelial cells is not driven by AhR-dependent signals from bone marrow-derived cells. Thus, the lung contains important targets of AhR regulation, which likely influence a novel iNOS-mediated mechanism that controls IFN-γ production by phagocytic cells. This suggests that AhR activation changes the response of lung parenchymal cells, such that regulatory pathways in the lung are cued to respond inappropriately during infection. These findings also imply that environmental factors may contribute to differential susceptibility to influenza virus and other respiratory pathogens.

Memory CD8+T Cells Are Sufficient To Alleviate Impaired Host Resistance to Influenza A Virus Infection Caused by Neonatal Oxygen Supplementation

“…Leukocytes from the airways were collected by bronchoalveolar lavage (BAL) with cold RPMI 1640 containing 1% BSA as previously described (41). Leukocytes from the entire lung were obtained by digesting intact (i.e., not subjected to lavage) lungs with collagenase (RPMI 1640 medium containing 0.7 mg/ml collagenase A [Worthington Biochemical Corp.], 30 g/ml DNase I, 2.5% fetal bovine serum [FBS], and 10 mM HEPES) (29). Prior to instillation of the collagenase solution via the trachea, circulating leukocytes were removed from the pulmonary vasculature by perfusing 5 ml of PBS containing 2 mM EDTA via the right ventricle.…”

Invariant NKT cells reduce the immunosuppressive activity of influenza A virus–induced myeloid-derived suppressor cells in mice and humans

“…It has previously been shown that lungs of IAV-infected mice are infiltrated by neutrophils expressing CD11b and Gr-1 markers (39,40). Since it is known that alteration of cytokines during acute and chronic inflammations results in the expansion of ARG-1- and NOS-expressing MDSCs (i.e., CD11b + Gr-1 + cells) (10) and since cytokines and chemokines are elevated during influenza virus infection (3, 41), we measured the frequency and activity of MDSCs in the lungs of PR8-infected WT, Jα18 -/-, and CD1d -/-mice ( Figure 2A).…”

Multispectral imaging of hematopoietic cells: Where flow meets morphology

“…Darkness could be determined by minimum intensity and cragginess could be measured as a frequent change in the intensity of brightfield signal within the cells (Gradient RMS). ImageStream analysis of cell and nuclear shape combined with immunophenotype has been used by other investigators to define cells produced during ES cell differentiation, cells bound by natural killer cells, and which cells are producing IFN-gamma (Kim et al, 2007;Neff-LaFord et al, 2007;Woll et al, 2008). There are a growing number of investigators using the ImageStream to quantify colocalization of proteins or the extent of a protein's localization within the nucleus (Beum et al, 2006;Liu et al, 2007;Matsuda et al, 2007;Ramos et al, 2007).…”