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

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.