Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

Abstract

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1alpha, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12-24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.

Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

“…Concomitant with the activation of the adaptive immune responses, leukocytes are recruited to the lung and numerous soluble mediators, such as surfactant proteins, cytokines, and chemokines, are produced by infiltrating immune cells and structural cells of the lung (22)(23)(24)(25). Together, they help diminish viral replication, destroy infected cells, and promote tissue repair.…”

“…and tumor necrosis factor-a. These cytokines and chemokines were chosen because they stimulate leukocyte recruitment and are known to be induced during influenza A virus infection (22,26,27). In room air-exposed mice, MCP-1 levels increased within 24 hours of infection and became significantly elevated on Day 3 before declining to naive levels by Day 9 ( Figure 6A).…”

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

“…Female B6.AhR tm1Bra (AhR Ϫ/Ϫ ) mice were obtained by breeding AhR Ϫ/ϩ females with AhR Ϫ/Ϫ males. AhR Ϫ/Ϫ mice were bred at Washington State University and genotyped by PCR, as described previously (31). All mice were housed in microisolator cages in a specified pathogen-free facility at either Washington State University or the Trudeau Institute, and were provided food and water ad libitum.…”

“…We have investigated the mechanisms underlying the immunosuppressive effects of TCDD, and have shown previously that exposure of mice to TCDD impairs multiple facets of the immune response to influenza A virus, resulting in suppressed virus-specific IgG levels, enhanced pulmonary inflammation, and altered cytokine production in the lung and draining lymph nodes (25,30,31). Importantly, we have found that during primary infection, exposure to a single dose of TCDD suppresses the proliferation of CD8 ϩ T cells in the mediastinal lymph nodes (MLN), reduces their production of IFN-␥, and impairs the generation of CTL (25,30).…”

Cancer immunoediting and dioxin-activating aryl hydrocarbon receptor: a missing link in the shift toward tumor immunoescape?

“…56 AhR is expressed in bone marrowderived cells such as T-and B-lymphocytes, neutrophils, and macrophages, and findings generated using AhR-deficient mice indicate that the immunomodulatory effects of dioxin are AhR-mediated. [57][58][59] Exposure to dioxin leads to profound suppression of both humoral and cellular immune responses. 60 Dioxin-activated AhR suppresses T-cells, which are its primary targets, and mediates B-cell antibody response inhibition [61][62][63] and thymic involution, with consequent thymocyte loss, premature migration of T-cell progenitors, [64][65][66] and overexpression of FAS-L in thymic stromal cells, resulting in Tcell apoptosis induction.…”