Microglia are the tissue-resident macrophages in the central nervous system and are critically involved in immune defense, neural development and function, and neuroinflammation. The versatility of microglia has long been attributed to heterogeneity. Recent studies have revealed possible heterogeneity in human but not in murine microglia, yet a firm demonstration linking microglial heterogeneity to functional phenotypes remains scarce. Here, we identified two distinct microglial populations in adult zebrafish that differ in morphology, distribution, development, and function. The predominant population, phagocytotic microglia, which expresses ccl34b.1, is broadly distributed, amoeboid in shape, highly mobile, and phagocytotic. The other white matter–enriched ccl34b.1⁻ population, regulatory microglia, has ramified protrusions but has limited mobility and phagocytosis capability. These functional differences are further supported by distinct transcriptomes and responses to bacterial infection, where ccl34b.1⁺ microglia function in tissue clearance and ccl34b.1⁻ microglia release immune regulators. Our study sheds light on the heterogeneity and functional diversification of microglia.

小胶质细胞是中枢神经系统中的组织驻留巨噬细胞，与免疫防御、神经发育和功能以及神经炎症密切相关。小胶质细胞的多功能性长期以来一直归因于异质性。最近的研究揭示了人类可能的异质性，但小鼠小胶质细胞中没有，但将小胶质细胞异质性与功能表型联系起来的坚定证据仍然很少。在这里，我们在成年斑马鱼中发现了两种不同的小胶质细胞群，它们在形态、分布、发育和功能上有所不同。表达ccl34b.1的主要群体吞噬性小胶质细胞分布广泛，呈变形虫状，具有高度移动性和吞噬性。另一种富含白质的ccl34b.1 ^-种群，调节性小胶质细胞，具有分枝突起，但流动性和吞噬能力有限。不同的转录组和对细菌感染的反应进一步支持了这些功能差异，其中ccl34b.1 ⁺小胶质细胞在组织清除中发挥作用，而ccl34b.1 ^-小胶质细胞释放免疫调节剂。我们的研究揭示了小胶质细胞的异质性和功能多样化。