Defective macrophage function in aquaporin-3 deficiency.

Macrophages play an essential role in innate immunity. We found that mouse resident peritoneal macrophages (mRPMs) express the aquaglyceroporin aquaporin-3 (AQP3) in a plasma membrane pattern. AQP3-deficient (AQP3(-/-)) mice showed significantly greater mortality than wild-type (AQP3(+/+)) mice in a model of bacterial peritonitis. To establish the cellular mechanism of the peritonitis phenotype, measurements were made of mRPM phagocytosis, migration, and water/glycerol permeability. We found significantly impaired engulfment of Escherichia coli and chicken erythrocytes in AQP3(-/-) vs. AQP3(+/+) mRPMs, as well as impaired migration of AQP3(-/-) mRPMs in response to a chemotactic stimulus. In AQP3(+/+) mRPMs, AQP3 was polarized to pseudopodia at the leading edge during migration and around the phagocytic cup during engulfment. Water and glycerol permeabilities in mRPMs from AQP3(-/-) mice were reduced compared to mRPMs from AQP3(+/+) mice. Cellular glycerol and ATP content were remarkably lower in AQP3(-/-) vs. AQP3(+/+) mRPMs, and glycerol supplementation partially rescued the reduced ATP content and impaired function of AQP3(-/-) mRPMs. These data implicate AQP3 as a novel determinant in macrophage immune function by a cellular mechanism involving facilitated water and glycerol transport, and consequent phagocytic and migration activity. This is the first study demonstrating involvement of an aquaporin in innate immunity. Our results suggest AQP3 as a novel therapeutic target in modulating the immune response in various infectious and inflammatory conditions.