Two phenotypically and functionally distinct microglial populations in adult zebrafish

Abstract

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.

Cellular Mechanisms Participating in Brain Repair of Adult Zebrafish and Mammals after Injury

“…In contrast, the positive role of microglia in zebrafish telencephalic regeneration has been recently highlighted [ 96 , 172 ]. Importantly, in contrast to mammalian microglia cells, for which recent transcriptomic analysis have shown a relative homogeneity during adulthood, zebrafish microglia can be separated into two subpopulations (ccl34b positive and negative) displaying different phenotypes and functions [ 95 ]. Wu et al raised the question of the functional specialization of microglial in fish linked to multiple rounds of genomic duplication [ 183 ].…”

“…In zebrafish, two microglial populations have been documented, differing in morphology, distribution, and functions [ 95 ]. The main population corresponds to phagocytotic microglia (ccl34b.1-positive) and is widely distributed, highly mobile, and phagocytic.…”

“…The main population corresponds to phagocytotic microglia (ccl34b.1-positive) and is widely distributed, highly mobile, and phagocytic. The less represented microglia population (ccl34b.1-negative) is ramified and exhibits only low mobility and phagocytic properties [ 95 ]. As part of the inflammatory response, microglia appear to be among the first cells being recruited and activated following brain injury [ 61 , 66 , 91 ].…”

Dendrimer-targeted immunosuppression of microglia reactivity super-accelerates photoreceptor regeneration kinetics in the zebrafish retina

“…Single-cell transcriptomic studies have revealed signatures of neurodegenerative disease-associated microglia (DAM) (35,36) and bulk RNA studies have delineated regeneration-associated microglia (RAM; (37)). That functionally discrete microglia subtypes exist was recently confirmed in a mouse model of retinal degeneration (38) and in zebrafish brain (39). AO-LLSM imaging data suggests an extension of this concept, with functional divergence arising even among neighboring microglia.…”

A Comparative Biology of Microglia Across Species

“…However, this heterogeneity pales when compared to the heterogeneity in humans ( Geirsdottir et al, 2020 ). Furthermore, microglial heterogeneity is recognized in zebrafish ( Wu et al, 2020 ). However, the extent to which these heterogenous microglial populations are already present in ancestral species remains to be adequately clarified.…”