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Activation of Alveolar Macrophages with Interferon-and#195;and#381;and#194;and#179; Promotes Antioxidant Defenses via the Nrf2-ARE Pathway | OMICS International | Abstract
ISSN: 2155-9899

Journal of Clinical & Cellular Immunology
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Research Article

Activation of Alveolar Macrophages with Interferon-γ Promotes Antioxidant Defenses via the Nrf2-ARE Pathway

Bashar S Staitieh1*#, Eduardo E Egea1#, Xian Fan1, Nnamdi Azih2, Wendy Neveu1 and David M Guidot1,3
1Division of Pulmonary, Allergy & Critical Care Medicine, Emory University School of Medicine, United States
2Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, United States
3Atlanta VA Medical Center, Decatur, United States
#denotes shared first authorship
Corresponding Author : Bashar S Staitieh, MD
Division of Pulmonary
Allergy, Critical Care Medicine and Sleep Medicine
Emory University School of Medicine
615 Michael Street, Suite 205, Atlanta, GA 30322, United States
Tel: (404) 712-2547
Fax: (404) 712-2974
E-Mail: [email protected]
Received: August 17, 2015; Accepted: October 27, 2015; Published: October 30, 2015
Citation: Staitieh BS, Egea EE, Fan X, Azih N, Neveu W, et al. (2015) Activation of Alveolar Macrophages with Interferon-γ Promotes Antioxidant Defenses via the Nrf2-ARE Pathway. J Clin Cell Immunol 6:365. doi:10.4172/2155-9899.1000365
Copyright: © 2015 Staitieh BS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Macrophage phenotype and function is dependent on the underlying microenvironment. Many diseases are accompanied by abnormal shifts in macrophage polarization state that limit the ability of the cells to become innate immune effectors. Previous work in the field suggests that chronic alcohol ingestion, which is associated with a shift away from innate immune effector macrophages, is also associated with a deficient response to oxidative stress. We therefore hypothesized that the optimal response to oxidative stress was dependent on the ability of the macrophage to become an innate immune effector cell. To investigate this hypothesis, we first confirmed that we could reproducibly polarize NR8383 cells (a rat alveolar macrophage cell line) into the prototypical M1 and M2 states (using IFN-γ and IL-4, respectively). We then tested the polarized cells for their ability to scavenge reactive oxygen species generated by glucose oxidase (GOX) using the Amplex red assay and found that IFN-γ-polarized cells had greater scavenging capacity. To elucidate the mechanism of the enhanced response to oxidative stress, we then assessed key components of the anti-oxidant response; specifically, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the master transcription factor responsible for the cellular response to oxidative stress, and one of its downstream effectors, glutamate-cysteine ligase catalytic subunit (GCLC). We found that both proteins were significantly upregulated in the IFN-γ-polarized cells. To confirm that Nrf2 is an integral component of this improved anti-oxidant response, we transfected IFN-γ-polarized cells with either silencing RNA to Nrf2 or control silencing RNA and found that hydrogen peroxide scavenging was significantly impaired in the si-Nrf2-treated cells. Further, transfecting untreated cells with si-Nrf2 polarized them toward the M2 phenotype in the absence of IL-4, suggesting a mechanistic role for Nrf2 in macrophage polarization. We then confirmed several of our key experiments in primary rat alveolar macrophages cells. Taken together, these findings suggest that the M1 polarization state is necessary for the optimal response to oxidative stress in the macrophage, and that this response is mediated through Nrf2 and its downstream effectors.

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