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Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice

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Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice This information is current as Christine K. Wong, Candice A. Smith, Koji Sakamoto, of September 28, 2021. Naftali Kaminski, Jonathan L. Koff and Daniel R. Goldstein J Immunol published online 23 June 2017 http://www.jimmunol.org/content/early/2017/06/23/jimmun ol.1700397 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/06/23/jimmunol.170039 Material 7.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 23, 2017, doi:10.4049/jimmunol.1700397 The Journal of Immunology Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice Christine K. Wong,*,†,1 Candice A. Smith,‡,1 Koji Sakamoto,* Naftali Kaminski,* Jonathan L. Koff,* and Daniel R. Goldstein*,†,‡,x Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts im- munity to influenza lung infection remain unclear. We employed a murine model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically downregulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces Downloaded from defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses. The Journal of Immunology, 2017, 199: 000–000. lder people exhibit increased morbidity and mortality and reduced inflammasome activity (4–8). Despite these reports, in response to respiratory viral infections (1, 2). As the there remains controversy as to the impact of aging on the suscep- http://www.jimmunol.org/ O number of older adults increases, the incidence of morbid tibility to influenza viral infections in murine models. On one hand, complications from respiratory infections also grows. Indeed, prior reports indicate that aged mice (age range 18–26 mo) exhibit during the years 1988–2002, people .65 y of age exhibit a 20% higher mortality, morbidity, and lower viral clearance than do young increase in hospitalization rates for community acquired pneumonia mice during influenza viral lung infection (4, 6, 7, 9). On the other (3). Hence, discerning how aging modifies immunity to influenza hand, a recent study documented that aged (24–26 mo old) mice virus on a molecular basis is critical to developing novel therapies infected with influenza virus exhibit significantly lower mortality and treatments that will protect older adults from respiratory and higher viral clearance than do young mice (10). Additionally, the infection. critical cellular mechanisms by which aging alters the host response Experimental studies have documented several age-associated to influenza viral lung infection remains unclear. by guest on September 28, 2021 alterations during influenza viral infection that include reduced In this study, we used dose titrating aliquots of influenza virus to antiviral CD8+ T cell responses, decreased NK cell function, al- evaluate how aging affects mortality and lung damage during in- tered PG production, increased expansion of regulatory T cells, fluenza viral infection. We identified alveolar macrophages (AM), key tissue resident macrophages for lung homeostasis (11), as critical for mortality during influenza viral lung infection with *Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520; aging. The transcriptional signatures of AM from young and ad- †Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520; ‡Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; vanced aged mice were substantially different: we found that 3545 and xInstitute of Gerontology, University of Michigan, Ann Arbor, MI 48109 genes were significantly altered with aging and that cell cycle 1C.K.W. and C.A.S. contributed equally to this work. pathways were markedly downregulated. Prior to and during in- ORCIDs: 0000-0001-7440-1809 (C.A.S.); 0000-0003-4567-7771 (D.R.G.). fection, advanced aged mice exhibited 2-fold lower concentrations Received for publication March 16, 2017. Accepted for publication May 24, 2017. of AM. Functionally, AM from advanced aged mice were im- This work was supported by National Institutes of Health Grant AG028082 and in paired in scavenging apoptotic neutrophils, displayed selective part by National Institutes of Health Grant HL130669 (to D.R.G.). C.A.S. is sup- downregulation of a key scavenging receptor, CD204, and exhibited ported by National Institutes of Health Grant T32-HL007853. defects in limiting lung damage. Therefore, our study has found that C.K.W., J.L.K., C.A.S., and D.R.G. designed experiments; C.K.W. and C.A.S. con- aging impairs the intrinsic function of AM to limit lung damage ducted the in vivo and in vitro experiments; C.K.W., C.A.S., and D.R.G. analyzed data; K.S. and N.K. conducted and analyzed microarrays and performed the micro- during influenza viral lung infection. array statistical analyses; D.R.G. and C.A.S. wrote the paper; C.K.W. and J.L.K. read and edited the paper; and D.R.G. procured funding. Materials and Methods The microarray data presented in this article have been submitted to the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/geo/) under ac- Mice and in vivo viral infection cession number GSE84901. C57BL/6 mice of 2–4 mo (representative weight, 26 6 2 g [SD]), 16 mo Address correspondence and reprint requests to Dr. Daniel R. Goldstein, University (36 6 3.7 g), and 22–24 mo of age (33 6 2.5 g) were obtained from the of Michigan, NCRC B020-209W, 2800 Plymouth Road, Ann Arbor, MI 48104. National Institute of Aging rodent facility. Mice were infected with puri- E-mail address: [email protected] fied human influenza virus A/Puerto Rico/8/34 (H1N1) (PR8) (Advanced The online version of this article contains supplemental material. Biotechnologies, Eldersburg, MD) as previously reported (12). Mice were Abbreviations used in this article: AM, alveolar macrophage; BAL, bronchoalveolar anesthetized with isoflurane and instilled intranasally (i.n.) with 50 mlof lavage; DPI, day postinfection; FDR, false discovery rate; i.n., intranasal(ly); LDH, PBS containing the indicated dose of PR8 virus or 50 ml of PBS control. lactate dehydrogenase; MPO, myeloperoxidase; RSV, respiratory syncytial virus. Following infection, mice were monitored daily for changes in weight, clinical scores, and mortality. Clinical scores were determined by ruffled Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 fur, activity, hunched back, and mortality (Table I), specifically mice were www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700397 2 AGING AND INFLUENZA VIRAL INFECTION euthanized when 30% of their original weight was lost, which was re- F4/80, and CD11c as previously reported (13, 14). The Siglec-F Ab was corded as death in survival experiments. No animals were used in the study purchased from BD Biosciences. All other Abs were purchased from when they displayed evidence of infection or other illnesses prior to PR8 eBioscience. Flow cytometry data were acquired on an LSR II (BD Bio- infection. Both the Yale University and University of Michigan Institu- sciences) and analyzed with FlowJo (Ashland, OR) software. tional Animal Care and Use Committees approved the use of animals in To assess the AM proliferation rate, single-cell suspensions were prepared this study. Prior to viral infection, all mice were kept in pathogen-free and stained as described above followed by intracellular Ki67 (allophyco- conditions. cyanin) (eBioscience) staining according to the manufacturer’s protocol. For sorting of AM, single-cell suspensions were prepared as above from Sample collection and preparation lung homogenates and stained with CD45 (allophycocyanin-Cy7), CD11c (FITC), F4/80 (Pacific Blue) and Siglec-F (PE). Cells were sorted in PBS Tissues were harvested from PBS-instilled or PR8-infected mice (n = 3–5 containing 1% BSA and 2 mM EDTA on a FACSAria (BD Biosciences) per time point for each experiment) at 1, 3, 6, and 9 d postinfection (DPI). and collected into HBSS supplemented with 1% BSA and 2 mM EDTA for Each time point was repeated at least three times independently. After adoptive transfer or TRIzol (Invitrogen, Carlsbad, CA) for RNA extraction euthanasia, the bronchoalveolar lavage (BAL) was obtained by washing (see below). the lungs twice with 1 ml of cold sterile 13 PBS. To harvest lungs, the chest cavity was opened and the lungs were removed and flash frozen in AM adoptive transfer liquid nitrogen. FACS-sorted AM were centrifuged at 5000 rpm for 5 min, resuspended in Assessment of tissue injury PBS, and 3 3 105 cells were transferred into recipient mice via i.n.
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