Autophagy in macrophages curtails IL-1α-mediated immune priming against lung infections

Host resistance to infection is initially determined by how well primed the innate immune system is to respond on first exposure to an invader, yet the mechanisms underlying this priming remain incompletely understood. Here we found that basal autophagy suppressed the expression of Il1a in alveolar macrophages (AMs) and an otherwise protective innate immune priming against Staphylococcus aureus and influenza A virus (IAV), independently of the microbiome and adaptive immunity. Inactivating autophagy genes in AMs led to elevated expression of IL-1α in AMs, which subsequently enhanced IL-1R-MyD88 signaling in neutrophils and increased the recruitment of myeloid cells to the lung. As a result, autophagy-deficient mice showed more efficient clearance of S. aureus along with reduced lung damage and inflammation. Similar to genetic inactivation of autophagy, overexpression of IL-1α in AMs conferred broad spectrum protection against S. aureus and IAV, suggesting a possible strategy to fine-tune immune responses to combat important respiratory infections.