Most tissues harbor a substantial population of resident macrophages. Here, we elucidate a functional link between the Slc7a7 cationic amino acid transporter and tissue macrophages. We 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 in other tissues, at stages where macrophages have to engulf many cell corpses, whether due to developmental or experimentally triggered cell death. We found that Slc7a7 is the main cationic amino acid transporter expressed in macrophages of zebrafish larvae, and that its expression is induced in tissue macrophages within 1–2 h upon efferocytosis. Our data indicate that 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.

大多数组织都含有大量常驻巨噬细胞。在这里，我们阐明了 Slc7a7 阳离子氨基酸转运蛋白和组织巨噬细胞之间的功能联系。我们发现了一种由于slc7a7基因突变而缺乏小胶质细胞的突变斑马鱼。我们发现，在 Slc7a7 缺陷的幼虫中，巨噬细胞确实进入视网膜和大脑成为小胶质细胞，但随后在神经元凋亡的发育波中死亡，这触发了巨噬细胞的强烈的细胞工作。类似的巨噬细胞死亡发生在其他组织中，在巨噬细胞必须吞噬许多细胞尸体的阶段，无论是由于发育还是实验触发的细胞死亡。我们发现Slc7a7是斑马鱼幼虫巨噬细胞中表达的主要阳离子氨基酸转运蛋白，并且其表达在胞吞作用后1-2小时内在组织巨噬细胞中被诱导。我们的数据表明，Slc7a7 不仅对小胶质细胞至关重要，而且对任何稳定的胞质组织巨噬细胞也至关重要，并且 slc7a7基因诱导是一种适应性反应，使它们能够应对大量死亡细胞的分解代谢，而不损害其自身的活力。