Microglia, a type of neuronal support cells, function primarily as immune cells in the central nervous system (CNS). They mediate the immune response by acting as macrophages to clear cellular debris, dead neurons, and infectious agents from the nervous tissue through the process of phagocytosis (cell eating). When microglia are activated, they transform from a surveillance state to an effector state, where microglia serve multiple roles in both the innate (non-specific) and adaptive (specific) immune system. If these immune responses are improperly controlled, microglial activation can be a double-edged sword, bringing protective and damaging effects on the CNS.

On top of their primary function as scavengers, microglia also play other roles in neural development, glial (non-neuronal) cell regulation, and blood vessel formation. How microglia manage to coordinate between all these roles is not fully understood. However, the versatility of microglia is thought to be related to their heterogeneous populations; in other words, different subtypes of microglia exist in the CNS to serve distinct functions.

Recent studies have revealed that microglia heterogeneity exists in humans but not in mice, hamsters, sheep, marmosets, and macaques. Using zebrafish as an animal model, Prof. Zilong Wen and his research team identified two distinct microglial populations – the phagocytotic microglia and regulatory microglia. Their findings were published in the journal Science Advances on Nov 18, 2020.

The collection of genes activated in zebrafish microglia are very similar to other mammals, and these microglia are also fully capable of responding to danger signals, clearing dying neurons, and fine-tuning neuronal activity. Prof. Wen and his team created a genetically modified zebrafish that exhibits fluorescent green when ccl34b.1 is expressed and then analyzed the transcriptomes (all gene readouts present in cells), behavior, and phagocytosis ability. They found that there are two distinct microglial populations in adult zebrafish:

• The phagocytotic microglia: predominant population, ccl34b.1⁺, broadly distributed, amoeboid in shape, highly mobile, and phagocytotic.
• The regulatory microglia: white matter–enriched, ccl34b.1⁻, ramified protrusions, limited mobility and phagocytosis capability.

Furthermore, these two populations of microglia respond differently to bacterial infection, where ccl34b.1⁺ microglia function in tissue clearance and ccl34b.1⁻ microglia release immune regulators.

This study is the first evidence of microglia subtypes in the vertebrate adult CNS and provides fresh insights into the evolution of microglial function. 

Acute brain slice culture of double transgenic TgBAC(ccl34b.1:eGFP);Tg(mpeg1:DsRedx) fish

Journal Reference:

Wu S, Nguyen LTM, Pan H, Hassan S, Dai Y, Xu J, Wen Z. Two phenotypically and functionally distinct microglial populations in adult zebrafish. Sci Adv. 2020 Nov 18;6(47):eabd1160. doi: 10.1126/sciadv.abd1160.