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Page 14 Yanguas-Casás. Neuroimmunol Neuroinflammation 2020;7:13-22 I http://dx.doi.org/10.20517/2347-8659.2019.31

we aim to summarize the sex differences in functional responses of microglia described thus far and their
relevance in pathology.

MICROGLIA
[2]
Microglia represent 10%-15% of the cells in the brain . In recent years, microglia functions have
extensively widened, ranging from mere local immune defense of the CNS to being key players in brain
development and physiology. They have been shown to regulate dynamic surveillance of the environment
[3-6]
through their active processes, maintaining homeostasis and modulating neuroinflammation . They also
mediate phagocytosis and clearance of debris and apoptotic cells in disease and neurogenic niches [5,7-10] ,
shape brain development through synapse pruning, and allow brain wiring of neuronal circuits [11-13] .

Unlike most cell types in the CNS, microglia proceed from myeloid precursors that migrate from the
yolk sack to the CNS in early embryological stages [Embryonic Day 8.5 (E8.5)] [2,14] , before the closure
of the blood-brain barrier, which occurs around E13-E14.5 in mice [14,15] . Interestingly, microglial brain
colonization during embryonic development is highly conserved across vertebrate species [16-19] .

Microglial lineage differs from that of macrophages, as it is driven by the cytokine macrophage colony
stimulating factor (M-CSF), as well as the transcription factors Pu.1, Irf8, and Sall1 [14,20,21] . Microglia are
self-renewed from local proliferation of CNS resident cells, and the turnover is relatively low in both
humans and rodents. This suggests that these cells are likely to be primed, or even have a memory, due
to the different events they are exposed to through their lifespan [22-24] . This microglia priming will be
[25]
determinant in their responses, both in physiological conditions and in disease .

[26]
Microglia represent most of the fetal glial population, especially in early developmental stages . Microglia
roles at this time are likely to be sex-specific as sex differences may arise as early as hematopoiesis in the
embryonic yolk sac or when CNS colonization occurs during early embryonic development [26-28] . Moreover,
male and female microglia follow temporarily different trajectories during development [29,30] . Microglia
influence sexual differentiation; indeed, masculinization of the brain is dependent on the activation stage of
these cells [28,31-34] .

Fetal gonads develop early in development, and in males are fully active (except for spermatogenesis)
by mid to late gestation, showing a surge in fetal testis androgen production beginning the last few days
of gestation and enduring until shortly after birth in rodents. In primates, androgen production occurs
from the end of the first trimester and well into the second with another peak at birth [35,36] . Once in the
brain, testosterone (T) can be either aromatized to estradiol (E2) or 5-α reduced to dihyrdotestosterone
(DHT). Both T and DHT induce some masculine endpoints but it is E2 that is the dominant masculinizing
hormone in the rodent brain, through a prostaglandin E2 (PGE2)-mediated process [37,38] . Morphologically,
in certain sex differentiated brain regions, such as the preoptic area, males have more microglia with an
“activated” morphology characterized by an increase in cell body size and a decrease in process length and
[33]
branching .
Recent studies have demonstrated that microglia density and phenotype vary between male and female
rodents in several brain areas [33,39,40] . Mid adolescent changes lead to a higher blood flow in women
compared to men, which is maintained throughout life until the 60s, when this difference is milder.
These differences in blood flow may play a role in differential microglia density in certain brain areas [41-43] .
Despite this, not much attention has been paid to the relevance of sex differences in blood flow or
vasculature in differential microglia infiltration during fetal development. Subtle changes in the timing
and density of microglia arrival to certain brain regions, as a result of differential blood flow, would lead to
differential interaction of these cells with progenitors at different stages of microglia or neural progenitor