Sugar Alcohols of Polyol Pathway Serve as Alarmins to Mediate Local-Systemic Innate Immune Communication in...

Interorgan immunological communication is critical to connect the local-systemic innate immune response and orchestrate a homeostatic host defense. However, the factors and their roles in this process remain unclear. We find Drosophila IMD response in guts can sequentially trigger a systemic IMD reaction in the fat body. Sugar alcohols of the polyol pathway are essential for the spatiotemporal regulation of gut-fat body immunological communication (GFIC). IMD activation in guts causes elevated levels of sorbitol and galactitol in hemolymph. Aldose reductase (AR) in hemocytes, the rate-limiting enzyme of the polyol pathway, is necessary and sufficient for the increase of plasma sugar alcohols. Sorbitol relays GFIC by subsequent activation of Metalloprotease 2, which cleaves PGRP-LC to activate IMD response in fat bodies. Thus, this work unveils how GFIC relies on the intermediate activation of the polyol pathway in hemolymph and demonstrates that AR provides a critical metabolic checkpoint in the global inflammatory response.