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Alveolar Macrophage Expression and Downstream Signaling in The The Journal of Immunology Chronic Ethanol Ingestion in Rats Decreases Granulocyte-Macrophage Colony-Stimulating Factor Receptor Expression and Downstream Signaling in the Alveolar Macrophage1 Pratibha C. Joshi,*† Lisa Applewhite,*† Jeffrey D. Ritzenthaler,† Jesse Roman,*† Alberto L. Fernandez,*† Douglas C. Eaton,‡ Lou Ann S. Brown,§ and David M. Guidot2*† Although it is well recognized that alcohol abuse impairs alveolar macrophage immune function and renders patients susceptible to pneumonia, the mechanisms are incompletely understood. Alveolar macrophage maturation and function requires priming by GM-CSF, which is produced and secreted into the alveolar space by the alveolar epithelium. In this study, we determined that although chronic ethanol ingestion (6 wk) in rats had no effect on GM-CSF expression within the alveolar space, it significantly decreased membrane expression of the GM-CSF receptor in alveolar macrophages. In parallel, ethanol ingestion decreased cellular expression and nuclear binding of PU.1, the master transcription factor that activates GM-CSF-dependent macrophage functions. Furthermore, treatment of ethanol-fed rats in vivo with rGM-CSF via the upper airway restored GM-CSF receptor membrane expression as well as PU.1 protein expression and nuclear binding in alveolar macrophages. Importantly, GM-CSF treatment also restored alveolar macrophage function in ethanol-fed rats, as reflected by endotoxin-stimulated release of TNF-␣ and bacterial phagocytosis. We conclude that ethanol ingestion dampens alveolar macrophage immune function by decreasing GM-CSF receptor expression and downstream PU.1 nuclear binding and that these chronic defects can be reversed relatively quickly with rGM-CSF treatment in vivo. The Journal of Immunology, 2005, 175: 6837–6845. or over a century, alcohol abuse has been well recognized tion, or poor oral hygiene. However, the precise mechanisms by as a significant risk factor for serious pulmonary infec- which chronic ethanol ingestion impairs alveolar macrophage F tions. For example, alcoholic patients are at increased risk function are poorly understood. for infection with necrotizing Gram-negative pathogens such as Within the alveolar space, relatively undifferentiated circulating Klebsiella pneumoniae (1) or to develop bacteremia and shock monocytes are recruited and undergo terminal maturation and dif- from typical pathogens, most notably Streptococcus pneumoniae ferentiation into alveolar macrophages in response to stimulation (2). The mechanisms by which alcohol abuse increases the risk of by GM-CSF. GM-CSF is a 23-kDa protein that was originally pneumonia are likely multiple and include increased risk of aspi- isolated from mouse lung extracts but was named because of its ration of oropharyngeal flora, decreased mucociliary clearance of potent effects on bone marrow development (fully reviewed in Ref. bacterial pathogens from the upper airway, and impaired pulmo- 11). However, when a GM-CSF knockout mouse was constructed nary host defenses. Perhaps the most prominent effects on host a little more than a decade ago, the phenotype was unexpected defense involve the alveolar macrophage, the first cellular line of (12). Specifically, the absence of GM-CSF expression had no dis- defense against pathogens within the lower airways. In experimen- cernible effect on hematopoiesis. However, the mice developed a tal models, chronic ethanol ingestion suppresses chemokine re- severe pulmonary phenotype that closely resembled pulmonary al- sponses and pathogen clearance from the airways (3–9) and im- veolar proteinosis (PAP)3 in humans. Insights from the mouse pairs alveolar macrophage innate immunity, including phagocytic studies ultimately led to the recognition that most patients with function and IL-12 secretion in response to endotoxin (10). Such PAP have acquired Abs to GM-CSF that neutralize the protein studies support the evolving recognition that alcohol abuse has within the alveolar space and prevent binding to its receptor on the specific effects on innate immune function within the lower air- alveolar macrophage membrane (13). Although PAP was first de- ways and that the increased risk of pneumonia in these patients scribed based on the accumulation of surfactant proteins and phos- cannot be ascribed solely to factors such as malnutrition, aspira- pholipids within the alveolar space, we now recognize that it is due to global defects in GM-CSF-dependent alveolar macrophage function that include impaired surfactant recycling, as well as de- *Atlanta Veterans Affairs Medical Center, †Department of Medicine, ‡Department of Physiology, and §Department of Pediatrics, Emory University School of Medicine, pressed innate immune functions (13). Therefore, patients with Atlanta, GA 30322 PAP have an acquired, functional deficiency in GM-CSF (as op- Received for publication May 11, 2005. Accepted for publication September 1, 2005. posed to a genetic mutation) that produces alveolar macrophage The costs of publication of this article were defrayed in part by the payment of page dysfunction. With this background, we hypothesized that alcohol- charges. This article must therefore be hereby marked advertisement in accordance mediated suppression of alveolar macrophage function could in- with 18 U.S.C. Section 1734 solely to indicate this fact. volve a functional defect in GM-CSF expression and/or signaling 1 This work is supported by National Institutes of Health, National Institute on Alcohol within the alveolar space. Abuse and Alcoholism P50 AA013757 and a Veterans Affairs Merit Review (to D.M.G.). 2 Address correspondence and reprint requests to Dr. David M. Guidot, Atlanta Vet- erans Affairs Medical Center (151-P), 1670 Clairmont Road, Decatur, GA 30033. 3 Abbreviations used in this paper: PAP, pulmonary alveolar proteinosis; GM- E-mail address: [email protected] CSFR␣, GM-CSF receptor ␣ subunit; GM-CSFR␤, GM-CSF receptor ␤ subunit. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 6838 ETHANOL AND GM-CSF SIGNALING GM-CSF is produced by the alveolar epithelium and binds to and GM-CSF, (sense) 5Ј-TCTGAGCCTCCTAAATGAC-3Ј, and (anti- specific GM-CSF receptors on the plasma membrane of the alve- sense) 5Ј-CATTTCTGGACCGGCTTC-3Ј. olar macrophage and thereby activates an intracellular signaling Rat GM-CSF primers were designed in our lab and were obtained from Sigma-Genosys. Rat G3PDH primers were purchased from Promega. Mo- pathway that ultimately leads to expression and nuclear binding of lecular mass marker HaeIII digest with fragment sizes 1358–72 bp was the transcription factor PU.1 (13). PU.1 is a member of the ETS purchased from Amersham Biosciences. family of transcription factors previously identified as a master Determination of GM-CSF protein levels in lung lavage fluid transcription factor in the proliferation and differentiation of my- eloid cells (14), and its expression is lost in alveolar macrophages In selected experiments, rat lungs were lavaged via a tracheostomy tube ϫ Ϯ both in patients with PAP and in GM-CSF knockout mice (11, 15). with saline (5 cc 3). The recovered lavage fluid (12 1 cc in all cases) was centrifuged at 1500 ϫ g for 10 min, and GM-CSF levels in the su- Lung-specific transgenic expression of GM-CSF in the type II cells pernatants were determined by a rat-specific ELISA (R&D Systems). The of these mice restores PU.1 expression and normalizes alveolar lower limit of detection was 10 pg/ml. Data are reported as total amount (in macrophage function (16). In fact, constitutive expression of PU.1 nanograms) of GM-CSF present in the lung lavage fluid. in alveolar macrophages of GM-CSF-deficient mice by transfec- Flow cytometric detection of membrane and intracellular tion with a PU.1-containing vector completely normalizes alveolar receptor expression macrophage function (17), confirming the critical role for PU.1 in GM-CSF signal transduction. Thus, GM-CSF-dependent expres- Membrane and intracellular expression of GM-CSF receptors on alveolar macrophages were measured by an established protocol (19). Briefly, cells sion of PU.1 appears to be absolutely required for terminal matu- were incubated for 30 min at room temperature with rabbit polyclonal Abs ration and function of the alveolar macrophage. However, to our (Santa Cruz Biotechnology) to either the rat GM-CSF receptor ␣ or ␤ knowledge, the effects of ethanol ingestion on GM-CSF expression subunit or to an isotype-matched control Ab. Cells were washed to remove and/or signaling to the alveolar macrophage within the alveolar unbound Ab followed by 30 min incubation at room temperature with space have not been examined. Therefore, we examined GM-CSF secondary anti-rabbit Ab conjugated to FITC. For intracellular staining of the receptors, cells were first permeabilized with 0.1% saponin in PBS, expression and key elements of its signaling, namely GM-CSF followed by staining with the Ab. Cells were washed with PBS-saponin receptor expression and PU.1 expression, in our rat model of before adding FITC-conjugated secondary Ab (Santa Cruz Biotechnology). chronic ethanol ingestion. We then determined the effects of rGM- Cells were washed with PBS and were kept in the dark at 4°C until ana- CSF treatment in vivo on restoring GM-CSF signal responsive- lyzed. The labeled cells were analyzed by FACScan flow cytometer (BD Biosciences). Data are expressed both as percentage of cells positive for the ness, as well as innate immune function, in the alveolar macro- ␣ subunit or the ␤ subunit, as well
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