Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice

Abstract

Although microglial activation is associated with all CNS disorders, many of which are sexually dimorphic or age-dependent, little is known about whether microglial basal gene expression is altered with age in the healthy CNS or if it is sex-dependent. Analysis of microglia from the brains of 3 day (P3) - to 12 month-old male and female C57Bl/6 mice revealed distinct gene expression profiles during postnatal development that differ significantly from adulthood. Microglia at P3 are characterized by relatively high iNOS, TNFα and arginase-1 mRNA levels, whereas P21 microglia have increased expression of CD11b, TLR4 and FcRγI. Adult microglia (2-4 months) are characterized by low pro-inflammatory cytokine expression that increases by 12 months of age. Age-dependent differences in microglial gene expression suggest that microglia likely undergo phenotypic changes during ontogenesis, although in the healthy brain they did not exclusively express either M1 or M2 phenotypic markers at any time. Interestingly, microglia were sexually dimorphic only at P3 when females had higher expression of inflammatory cytokines than males, although there were no sex differences in estrogen receptor expression at this or any other time evaluated here. Compared to microglia in vivo, primary microglia prepared from P3 mice had considerably altered gene expression with higher levels of TNFα, CD11b, arginase-1 and VEGF suggesting that culturing may significantly alter microglial properties. In conclusion, age- and sex-specific variances in basal gene expression may enable differential microglial responses to the same stimulus at different ages, perhaps contributing to altered CNS vulnerabilities and/or disease courses.

Sex and regional differences in microglia morphology and complement receptor 3 are independent of constitutive neuroinflammatory protein concentrations in healthy mice

“…We observed that inflammatory proteins are present and detectable in the healthy cortex, however, the concentration of these proteins were similar among sex groups in adult mice. Similarly, a previous investigation determined that mRNA levels of VEGF, arginase, and IL10 measured from primary microglia collected from 4 month old male mice were similar between males and females (Crain et al, 2013). Based on these data, we surmise that neuroinflammatory protein concentrations have a minimal influence on observed differences in microglia morphology and CR3 in the cortex.…”

Quantification of Entry Phenotypes of Macrophage-Tropic HIV-1 across a Wide Range of CD4 Densities

“…Macrophages have been classified as either M1 or M2, with activated M1 macrophages having proinflammatory, antimicrobial phenotypes and M2 macrophages having anti-inflammatory, wound-healing phenotypes (reviewed in reference 45). It is now appreciated that even this dichotomy does not capture the full continuum of macrophage phenotypes (47) and that additional macrophage diversity is generated from the complex signaling environment (47) and from inherent differences, such as basal gene expression (48), that alter how cells respond to signals. Together, cellular ontogeny, signaling environment, activation state, and basal gene expression generate diverse macrophage populations capable of performing a variety of functions.…”

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

“…Multiple mechanisms can lead to motor neuron injury, which funnel into a final pathway or noncell-autonomous toxicity and neuroinflammation leading to motor neuron death [59][60][61][62][63]. In contrast, M2 produce high levels of antiinflammatory cytokines and neurotrophic factors including IL-4, IL-10, and insulin-like growth factor (IGF)-1 in addition other neruoprotection signals such as CD200 and fractalkine [51,60,[64][65][66][67][68].…”