Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways

Abstract

Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used are not known. We found that mouse microglia were derived from primitive c-kit(+) erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. These precursors developed into CD45(+) c-kit(lo) CX(3)CR1(-) immature (A1) cells and matured into CD45(+) c-kit(-) CX(3)CR1(+) (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia.

IRF8 is a transcriptional determinant for microglial motility

“…We have previously reported that IRF8 is expressed specifically in microglia in the CNS and plays a central role in regulating microglial gene expression [5]. Furthermore, recent studies have also shown that IRF8 is required for the full maturation of microglia [17] in addition to its physiological functions, including phagocytosis and cytokine production [18,19]. These observations led us to speculate that IRF8 may regulate microglial motility by controlling an expression pattern of microglial genes.…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…They arise in the brain from early development and persist into adulthood. A long-standing controversy regarding the ontology of microglia led to a view that a subset of primitive myeloid precursors localized in the yolk sac give rise to early microglia [35][36][37]. Microglial precursors express CX3CR1 and CD45 and travel to the neuroectoderm in a matrix metalloproteinase-8-and matrix metalloproteinase-9-dependent manner [36,38].…”

“…A long-standing controversy regarding the ontology of microglia led to a view that a subset of primitive myeloid precursors localized in the yolk sac give rise to early microglia [35][36][37]. Microglial precursors express CX3CR1 and CD45 and travel to the neuroectoderm in a matrix metalloproteinase-8-and matrix metalloproteinase-9-dependent manner [36,38]. Importantly, these are not exchanged with fetal liver or bone marrowderived hematopoietic stem cells and they possess selfrenewing capability under physiologic conditions [35,36,39,40].…”

“…Microglial precursors express CX3CR1 and CD45 and travel to the neuroectoderm in a matrix metalloproteinase-8-and matrix metalloproteinase-9-dependent manner [36,38]. Importantly, these are not exchanged with fetal liver or bone marrowderived hematopoietic stem cells and they possess selfrenewing capability under physiologic conditions [35,36,39,40]. The morphology and protein expression of microglia are not uniform, and this heterogeneity could explain differential microglial responses in different surroundings [41,42].…”

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

“…Microglia, the resident macrophages of the brain, are derived from early yolk sac macrophage progenitors (Ginhoux et al ., 2010; Kierdorf et al ., 2013). Under physiological conditions, there is negligible infiltration of peripheral monocytes to the brain parenchyma and the microglia population is likely sustained by self‐renewal (Ajami et al ., 2007).…”