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. P. Herbomel conceived and supervised the project, and obtained the funding. M. Tauzin isolated the cerise mutant, gave it its name, and conducted the initial phenotypic study. D L Demy, M. Carrère and R. Noche conducted most of the subsequent study, with the help of M. Le Bris and C. Baek during their respective Master internship; M. Yousfi contributed the 4C4/Pu.1 double immunostaining images. D L Demy performed the initial mapping of the mutation; I. Leshchiner & W. Goessling identified the slc7a7 mutation via deep sequencing of mutant vs. sibling genome pools. P. Herbomel and D L Demy wrote the paper.

Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature

“…Chronic renal injury could also be generated by inflammatory processes secondary to dysregulated immune activation caused by excess NO production (78). Efferocytosis is the process by which macrophages and other phagocytic cells remove apoptotic cells; recently Demy et al showed that y+LAT1 is expressed shortly after efferocytosis in microglia and other tissue resident macrophages allowing them to preserve their own viability during phagocytosis, defects in macrophage phagocytic function could contribute to both neurologic and immunologic finding in patients with LPI (79).…”