Scientists Find New Check on Runaway Inflammation in Macrophages

By studying mice and cultured macrophages in the lab, researchers have identified a previously unknown molecular brake on inflammation that shields these cells from osmotic stress. Their experiments unveil an unexpected role for the amino acid transporter SNAT2, suggesting that it acts as an important safeguard for macrophages as they fight infections and navigate the highly osmotic environment of inflamed tissues. Macrophages are a central pillar of the body's innate immune system and often reprogram themselves to fight off invading pathogens. This reprogramming involves shifts in several metabolic pathways, and usually triggers after the activation of a transcription factor named HIF-1α. Here, Shota Yasakura and colleagues performed genome-wide CRISPR screens to search for other molecular players that control the reprogramming of macrophages. They exposed macrophages to either low-oxygen conditions (hypoxia) or to the bacterial molecule LPS to mimic the presence of pathogens. The CRISPR screens revealed that SNAT2 – known primarily for its role in importing amino acids – inhibited the activation of HIF-1α and prevented metabolic reprogramming in mouse macrophages exposed to LPS, but not to hypoxia. Cells that lacked SNAT2 displayed signs of osmotic stress, metabolic reprogramming, and the activation of inflammasomes induced by LPS when exposed to highly osmotic conditions. Mice deficient in SNAT2 also experienced more active inflammatory responses when infected with the pathogenic bacterium Listeria monocytogenes, but cleared the infections more quickly. "Further investigation may provide therapeutic strategies for modulating macrophage activation through the control of small neutral amino acid metabolism and osmotic regulation for inflammatory diseases," Yasakura et al. speculate.