Legionella-Infected Macrophages Engage the Alveolar Epithelium to Metabolically Reprogram Myeloid Cells and Promote Antibacterial Inflammation

Abstract

Alveolar macrophages are among the first immune cells that respond to inhaled pathogens. However, numerous pathogens block macrophage-intrinsic immune responses, making it unclear how robust antimicrobial responses are generated. The intracellular bacterium Legionella pneumophila inhibits host translation, thereby impairing cytokine production by infected macrophages. Nevertheless, Legionella-infected macrophages induce an interleukin-1 (IL-1)-dependent inflammatory cytokine response by recruited monocytes and other cells that controls infection. How IL-1 directs these cells to produce inflammatory cytokines is unknown. Here, we show that collaboration with the alveolar epithelium is critical for controlling infection. IL-1 induces the alveolar epithelium to produce granulocyte-macrophage colony-stimulating factor (GM-CSF). Intriguingly, GM-CSF signaling amplifies inflammatory cytokine production in recruited monocytes by enhancing Toll-like receptor (TLR)-induced glycolysis. Our findings reveal that alveolar macrophages engage alveolar epithelial signals to metabolically reprogram monocytes for antibacterial inflammation.

Keywords: GM-CSF; IL-1R; Legionella; alveolar epithelium; immunometabolism; innate immunity; macrophages; monocytes.