Environmental Cues Improve IFN--mediated Resistance to Influenza via Down-Regulation of Glucocorticoid Signaling in Myeloid Cells

Environmental Cues Improve IFN--mediated Resistance to Influenza via Down-Regulation of Glucocorticoid Signaling in Myeloid Cells | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Environmental Cues Improve IFN--mediated Resistance to Influenza via Down-Regulation of Glucocorticoid Signaling in Myeloid Cells Philippe Blancou, Clara Panzolini, Mélanie Guyot, Julien Lavergne, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7970798/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Environmental cues profoundly influence host immunity, yet the impact of positive environmental signals on viral infections remains unclear. Here, we demonstrate that mice housed in an enriched environment (EE), characterized by enhanced sensory, cognitive, and social stimuli, show markedly improved survival following influenza A virus infection compared to mice maintained in a standard environment (SE). EE mice exhibited lower pro-inflammatory cytokine production, and delayed infiltration of inflammatory monocytes and neutrophils into the lungs, despite transiently higher viral replication. We found that EE housing enhances TLR3-induced secretion of type I interferon, which signaling is required to promote EE-mediated protection against influenza. Given glucocorticoids control of IFN-β, we interrogated the role of glucocorticoid receptor (GR) signaling in EE-mediated protection. EE mice displayed reduced glucocorticoid levels in both serum and lungs as compared to SE mice, consistent with their increased pulmonary IFN-β. We identified GR signaling as a critical negative regulator of IFN-β production by myeloid cells. Thus, genetic ablation of GR in LysM+ myeloid cells, or pharmacological blockade with RU-486, in SE mice restored influenza protection against influenza, phenocopying EE benefits. These findings highlight a neuroendocrine-immunological axis wherein environmental enrichment modulates host innate antiviral immunity by dampening glucocorticoid-mediated suppression of IFN-β production. Our study reveals a novel, non-pharmacological strategy to modulate the brain-immune interface for enhancing innate immunity as a therapeutic anti-viral modality. Biological sciences/Microbiology/Virology/Influenza virus Biological sciences/Immunology/Neuroimmunology nfluenza virus environment inflammatory monocyte type-1 interferon corticosterone glucocorticoid receptor neuroimmunology Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7970798","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":547529480,"identity":"7ddb6ae3-e407-457d-a067-3e49a8164bd5","order_by":0,"name":"Philippe 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