Page 21 - Read Online

Yanguas-Casás. Neuroimmunol Neuroinflammation 2020;7:13-22 I http://dx.doi.org/10.20517/2347-8659.2019.31 Page 17

A B

Figure 1. Physiological sex differences in male and female microglia. A: male microglia have an enlarged soma and more reactiveness
in physiological conditions than female microglia. These cells have more pro-inflammatory responses, higher migration capacity, and
enhanced MHCI, MHCII, and P2Y12 constitutive expression; B: female microglia, on the other hand, have a higher phagocytic capacity
and higher gene expression of cell repair and inflammatory control genes

female brains, whereas it is higher in the amygdala in male brains. Other areas, such as the cortex, striatum,
and cerebellum, show similar densities in both sexes at these stages. At later developmental stages (early
adulthood), there is a higher microglia density in the cortex, hippocampus, and amygdala of male brains,
while there are no differences in the striatum and cerebellum [39,92] .

Similar to cell density, significant regional heterogeneity has also been found in microglial structural
complexity. During development, the soma size of female microglia is larger in the cortex, hippocampus,
and amygdala, while there were no changes in microglia size in other areas [39,92] . However, in adult stages,
[39]
male microglia show enlarged somas throughout the brain .

Microglial phagocytic activity has been shown to be enhanced in early postnatal female microglia
compared with males in both mice and rats [89,93] . On the other hand, male microglia show a higher P2Y12
receptor expression and higher motility capacity at this time [89,94] . Interestingly, male microglia also show
higher MHCI and MHCII expression, as well as enhanced P2X receptor-mediated signaling, which are
indicative of more reactiveness than female microglia already under physiological conditions [Figure 1].
[39]

Functional sex differences in microglia may have important functional consequences for disease
progression. It is likely that each sex uses different mechanisms to achieve similar baseline functional states
adapted to their sex-specific environments, and therefore microglial cells would have equivalent cellular
[95]
functionality regardless the sex .
[83]
Recent work has shown that microglia contribute to sex differences in social behavior and further
research will determine to what extent microglia partake in the brain sexual dimorphism. How such
intrinsic differences contribute to disease susceptibility also remains to be elucidated [30,39] .

Sex differences in microglia responses in disease
Microglia dysfunction is implicated in every single brain disease. Unveiling microglia functional sex
differences in non-physiological states may explain differences in disease susceptibility that result from sex-