Microbiota-induced EI24 improves homeostasis but impedes function of alveolar macrophages via metabolic regulation

Lung microenvironment controls the homeostasis and function of alveolar macrophages (AMs), the major regulators of lung immunity, but the underlying mechanisms, particularly the role of microbiota, remain unclear. Here, with Lyz2creEi24fl/fl mice, we report that EI24 deficiency in macrophages disrupts AMs homeostasis but enhances their phagocytosis and inflammatory responses via metabolic rewiring. Consequently, Lyz2creEi24fl/fl mice exhibit resistance to viral infection and tumor metastasis in lung. Notably, EI24 expression in AMs is upregulated by commensal microbiota through TLR2/4 signaling. These data demonstrate that microbiota upregulates EI24 in AMs to favor their homeostasis, but it retards their immune surveillance function in the lung. Our study thus indicates that deleting EI24 enhances anti-viral and anti-tumor effects of macrophage-based immunotherapy. Regulation of alveolar macrophage function requires further investigation. The authors here show that EI24, elicited by commensal microbiota, decreases alveolar macrophage phagocytosis and inflammatory responses against lung infection and tumor metastasis, whereas targeting EI24 enhances anti-viral and anti-tumor effects of macrophages.