Abstract
In vertebrates, during an early wave of hematopoiesis in the yolk sac between embryonic day E7.0 and E9.0, cells of mesodermal leaflet addressed to macrophage lineage enter in developing central nervous system (CNS) and originate the developing native microglial cells. Depending on the species, microglial cells represent 5–20% of glial cells resident in adult brain. Here, we briefly discuss some canonical functions of the microglia, i.e., cytokine secretion and functional transition from M1 to M2 phenotype. In addition, we review studies on the non-canonical functions of microglia such as regulation of phagocytosis, synaptic pruning, and sculpting postnatal neural circuits. In this latter context the contribution of microglia to some neurodevelopmental disorders is now well established. Nasu-Hakola (NHD) disease is considered a primary microgliopathy with alterations of the DNAX activation protein 12 (DAP12)-Triggering receptor expressed on myeloid cells 2 (TREM-2) signaling and removal of macromolecules and apoptotic cells followed by secondary microglia activation. In Rett syndrome Mecp2-/- microglia shows a substantial impairment of phagocytic ability, although the role of microglia is not yet clear. In a mouse model of Tourette syndrome (TS), microglia abnormalities have also been described, and deficient microglia-mediated neuroprotection is obvious. Here we review the role of microglial cells in neurodevelopmental disorders without inflammation and on the complex role of microglia in developing CNS.
Highlights
Microglia are the resident innate immune cells of central nervous system (CNS)
After E16.5, while fetal erythrocytes, granulocytes and monocytes are replaced by hematopoietic stem cell (HSC)-derived cells, Kupffer cells, microglial cells and Langerhans cells persist as quite stable populations; instead, lung alveolar macrophages and gut associated-macrophages can be replaced in older mice (Gomez Perdiguero et al, 2015)
It should be highlighted that IL-6 can have both pro-inflammatory and anti-inflammatory outcomes and these effects depend on the simultaneous presence of other cytokines; microglial cells release IL-6 in early phases of CNS injury, and thereafter IL-6 acts on astrocytes to activate them to repair damaged tissue (Raivich et al, 1999) (Table 1)
Summary
Microglia are the resident innate immune cells of CNS. Upon completion of the blood-brain barrier, microglia become physically restricted to the brain as a long-living, autonomous cell population that retains the ability to divide and self-renew during life without any significant contribution from circulating blood cells (Ajami et al, 2007). Kitada and Rowitch reported that in gray and white matter, microglia show different expression patterns and this heterogeneity was highlighted in astrocytes and oligodendrocytes (Kitada and Rowitch, 2006). These differences may affect normal microglial function and induce a different response upon inflammatory stimuli (Hristova et al, 2010). Large-scale single cell RNA sequencing (RNA-seq) has confirmed this regional heterogeneity (Zeisel et al, 2015) Another issue is the behavior of microglia following activation. Any given population may develop altered microglial functions and succumb more quickly to the stimulus, or may respond more quickly and effectively upon a second challenge (Conde and Streit, 2006)
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