Lipid-gated monovalent ion fluxes regulate endocytic traffic and support immune surveillance

Abstract

Despite ongoing (macro)pinocytosis of extracellular fluid, the volume of the endocytic pathway remains unchanged. To investigate the underlying mechanism, we used high-resolution video imaging to analyze the fate of macropinosomes formed by macrophages in vitro and in situ. Na+, the primary cationic osmolyte internalized, exited endocytic vacuoles via two-pore channels, accompanied by parallel efflux of Cl− and osmotically coupled water. The resulting shrinkage caused crenation of the membrane, which fostered recruitment of curvature-sensing proteins. These proteins stabilized tubules and promoted their elongation, driving vacuolar remodeling, receptor recycling, and resolution of the organelles. Failure to resolve internalized fluid impairs the tissue surveillance activity of resident macrophages. Thus, osmotically driven increases in the surface-to-volume ratio of endomembranes promote traffic between compartments and help to ensure tissue homeostasis.

Microglial Corpse Clearance: Lessons From Macrophages

“…Microglia are also very active in surveilling the brain parenchyma with their highly motile processes (40,41) and this is believed to be essential for brain maintenance and protection and to be in close connection with neuronal activity (42,43). However, microglial motility may not be so unique, as late evidence suggests that other macrophages might also perform this type of surveillance in the intersticial space (44).…”

NCX1 represents an ionic Na+ sensing mechanism in macrophages

“…Our data show that extracellular Na + is able to impact on intracellular organelle formation via NCX1. Very recently, it turned out that subcellular distribution of Na + via two-pore channels plays an important role in controlling the volume of macropinosomes and, thereby, the cell size of MFs [53]. Determining how increases in extracellular Na + influence these subcellular processes requires further studies.…”

Phagocytosis by the Retinal Pigment Epithelium: Recognition, Resolution, Recycling

“…These cells are non-migratory and are therefore strategically positioned for phagocytic encounters. In some cases, resident phagocytes are uniformly distributed to optimally survey the whole tissue by probing the space between them (4,5). In other cases, they are localized to particular regions that favor their collection and engulfment of phagocytic loads [e.g.…”