The cationic amino acid exporter Slc7a7 is vital for and induced in tissue macrophages with sustained efferocytic activity

Abstract

Most tissues harbor a substantial population of resident macrophages. It is not quite known yet how their quite diverse phenotypes are shaped by the functions that they assume in each tissue. In this study, we elucidate a functional link between the Slc7a7 cationic amino acid transporter and tissue macrophages. We had identified a mutant zebrafish devoid of microglia due to a mutation in the slc7a7 gene. We found that in Slc7a7 deficient larvae, macrophages do enter the retina and brain to become microglia, but then die during the developmental wave of neuronal apoptosis, which triggers intense efferocytic work from them. A similar macrophage demise occurs at other tissues and stages whereby macrophages have to engulf many cell corpses, be it due to developmental or experimentally triggered cell death. We found that slc7a7 is by far the main cationic amino acid transporter gene expressed in macrophages of wild type zebrafish larvae, and that its expression is induced in tissue macrophages within 1-2 hrs upon efferocytosis. Our data altogether indicate that a high level of Slc7a7 is vital not only for microglia but also for any steadily efferocytic tissue macrophages, and that slc7a7 gene induction is one of the adaptive responses that allow them to cope with the catabolism of numerous dead cells without compromising their own viability.