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      Progesterone-Based Therapy Protects Against Influenza by Promoting Lung Repair and Recovery in Females

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          Abstract

          Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women’s health.

          Author Summary

          Worldwide, the use of hormonal contraceptives is on the rise as a primary intervention for improving women’s health outcomes through reduced maternal mortality and increased childhood survival. There are many hormone contraceptive formulations, all of which contain some form of progesterone. Although the effects of hormone contraceptives and progesterone, specifically, have been evaluated in the context of infections of the reproductive tract, the effects of progesterone at other mucosal sites, including the respiratory tract have not been systematically evaluated. We have made the novel observation that administration of progesterone to female mice depleted of progesterone confers protection against both lethal and sublethal influenza A virus infection. In particular, progesterone reduces pulmonary inflammation, improves lung function, repairs the damaged lung epithelium, and promotes faster recovery following influenza A virus infection. Progesterone causes protection against severe outcome from influenza by inducing production of the epidermal growth factor, amphiregulin, by respiratory epithelial cells. This study provides insight into a novel mechanistic role of progesterone in the lungs and illustrates that sex hormone exposure, including through the use of hormonal contraceptives, has significant health effects beyond the reproductive tract.

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          Most cited references45

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          Sex differences in autoimmune disease.

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            Innate lymphoid cells promote lung tissue homeostasis following acute influenza virus infection

            Innate lymphoid cells (ILCs), a recently identified heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine but whether ILCs can influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed CD90, CD25, CD127 and T1-ST2. Strikingly, mouse ILCs accumulated in the lung following influenza virus infection and depletion of ILCs resulted in loss of airway epithelial integrity, decreased lung function and impaired airway remodeling. These defects could be restored by administration of the lung ILC product amphiregulin. Collectively, these results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis following influenza virus infection.
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              IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions.

              The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33-dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG-epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                15 September 2016
                September 2016
                : 12
                : 9
                : e1005840
                Affiliations
                [1 ]W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                [2 ]Department of Environmental Health Sciences, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                [3 ]Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
                [4 ]Department of Biochemistry and Molecular Biology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                St. Jude Children’s Research Hospital, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: OJH SLK.

                • Formal analysis: OJH NL MSV.

                • Funding acquisition: AP SLK.

                • Investigation: OJH NL MSV DPR NW.

                • Methodology: AP WM SLK.

                • Project administration: SLK.

                • Resources: AP WM SLK.

                • Supervision: AP WM SLK.

                • Validation: OJH NL MSV DPR NW.

                • Visualization: OJH MSV.

                • Writing – original draft: OJH SLK.

                • Writing – review & editing: OJH NL MSV DPR NW AP WM SLK.

                [¤a]

                Current address: Nathachit Limjunyawong, The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, MD, USA

                [¤b]

                Current address: Dionne P. Robinson, Laboratory of Parasitic Diseases, National Institutes of Health, NIAID, Bethesda, MD, USA

                Author information
                http://orcid.org/0000-0002-1981-3162
                http://orcid.org/0000-0002-9540-6171
                http://orcid.org/0000-0002-6450-6452
                http://orcid.org/0000-0002-0730-5224
                Article
                PPATHOGENS-D-16-01281
                10.1371/journal.ppat.1005840
                5025002
                27631986
                c947bdd6-7ad9-4caa-87fc-808519fcf720
                © 2016 Hall 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.

                History
                : 7 June 2016
                : 2 August 2016
                Page count
                Figures: 7, Tables: 1, Pages: 22
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI112838
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI097417
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: HHSN272201400007C
                Award Recipient :
                This study was supported by grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (grant numbers AI112838 and HHSN272201400007C to SLK and AI097417 to AP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Orthomyxoviruses
                Influenza viruses
                Influenza A virus
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Orthomyxoviruses
                Influenza viruses
                Influenza A virus
                Medicine and health sciences
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                Orthomyxoviruses
                Influenza viruses
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                Biology and life sciences
                Organisms
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                Orthomyxoviruses
                Influenza viruses
                Influenza A virus
                Biology and Life Sciences
                Biochemistry
                Hormones
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                Progesterone
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                Medicine and Health Sciences
                Pulmonology
                Pulmonary Function
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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