Crosstalk between lung epithelial cells and myeloid cells in innate immune defense

Abstract

Abstract Pathogens have evolved a wide range of strategies to allow survival and subsequently cause disease in humans. However, it is still poorly understood how the immune system successfully overcomes pathogen-induced disturbance and enable robust immune responses against infection. The intracellular bacterium Legionella pneumophila has the ability to block global protein synthesis in target macrophages, but the host can still strongly evoke an IL-1-dependent inflammatory response that clears infection. Here, we show that IL-1 signals directly to alveolar epithelial cells, which potently drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by these cells. Importantly, GM-CSF-mediated JAK2/STAT5 signaling promotes inflammatory gene expression in myeloid cells. We found that STAT5 was enriched at the 5′ upstream regions of inflammatory cytokine genes. In addition, GM-CSF metabolically reprogrammed myeloid cells to undergo aerobic glycolysis, which was required for maximal inflammatory cytokine production. Our findings reveal that lung epithelial cells act as a key intermediary to facilitate communication between infected and bystander myeloid cells and orchestrate antimicrobial defense.