miR‐124 Contributes to the functional maturity of microglia

Abstract

During early development of the central nervous system (CNS), a subset of yolk-sac derived myeloid cells populate the brain and provide the seed for the microglial cell population, which will self-renew throughout life. As development progresses, individual microglial cells transition from a phagocytic amoeboid state through a transitional morphing phase into the sessile, ramified, and normally nonphagocytic microglia observed in the adult CNS under healthy conditions. The molecular drivers of this tissue-specific maturation profile are not known. However, a survey of tissue resident macrophages identified miR-124 to be expressed in microglia. In this study, we used transgenic zebrafish to overexpress miR-124 in the mpeg1 expressing yolk-sac-derived myeloid cells that seed the microglia. In addition, a systemic sponge designed to neutralize the effects of miR-124 was used to assess microglial development in a miR-124 loss-of-function environment. Following the induction of miR-124 overexpression, microglial motility and phagocytosis of apoptotic cells were significantly reduced. miR-124 overexpression in microglia resulted in the accumulation of residual apoptotic cell bodies in the optic tectum, which could not be achieved by miR-124 overexpression in differentiated neurons. Conversely, expression of the miR-124 sponge caused an increase in the motility of microglia and transiently rescued motility and phagocytosis functions when activated simultaneously with miR-124 overexpression. This study provides in vivo evidence that miR-124 activity has a key role in the development of functionally mature microglia.

Exosomes from NSC-34 Cells Transfected with hSOD1-G93A Are Enriched in miR-124 and Drive Alterations in Microglia Phenotype

“…In respect to miR-124 it was shown to promote microglia quiescence by diminishing M1 polarization and enhancing M2 phenotype (Ponomarev et al, 2011; Liu and Abraham, 2013), in particular the M2c microglia subset (Veremeyko et al, 2013). However, it is also a trigger of microglia functional maturity, at least during CNS development, where microglia evidence a reduced cellular motility and phagocytic ability (Svahn et al, 2016). Finally, miR-146a overexpression is found in M1, M2a, M2c, and senescent microglia subsets (Jiang et al, 2012; Cobos Jimenez et al, 2014).…”

How to reprogram microglia toward beneficial functions

“…Its forced expression downregulates pro‐inflammatory markers, while increases the expression of protective markers, as is the case of TGF‐β, Arg1, and FIZZ1 (Y. Sun et al, ; Ponomarev et al, ; S. Huang et al, ; Periyasamy et al, ) and reduces microglial phagocytic ability (Pinto, Cunha, Barbosa, Vaz, & Brites, ; Svahn, Giacomotto, Graeber, Rinkwitz, & Becker, ). The contribution of miR‐124 to homeostatic/anti‐inflammatory microglia functions relies on silencing of CCAAT/enhancer‐binding protein (C/EBP)‐α (P. Zhang et al, ), one of the major transcription factor that drives pro‐inflammatory microglia polarization (A. Yu et al, ).…”

The immune system as a novel regulator of sex differences in brain and behavioral development

“…Early prenatal stress disrupts the masculinization process in the hypothalamus via mediating effects on micro‐RNA expression in the brain (Morgan and Bale, ). Other work unrelated to stress has shown that micro‐RNAs, particularly mir‐124, regulate the progression of microglia from an activated, phagocytic phenotype to a mature, surveying phenotype in the developing brain (Ponomarev et al, ; Svahn et al, ). Thus, sex differences in microglia in the developing brain may depend on sex differences in micro‐RNAs, or sex differences in the response to stress may in turn depend on differential micro‐RNA regulation of microglia.…”