Table 3.

Preclinical studies examining sex-specific differences in microglia and astrocytes in the response to ischemic stroke

Study	Species and strain	Age	Key findings
Xiong et al. [131]	BALB/cJ and IL-4 KO (BALB/c-IL-4tm2Nnt/J) mice	10–12 weeks	IL-4 is neuroprotective in female mice. It prompts differentiation to the M2 (anti-inflammatory) microglia phenotype and reduced monocyte/macrophage infiltration into the ischemic brain
Seifert et al. [75]	C57BL/6 J mice	8–10 weeks	Post MCAO, female mice had smaller infarct volumes. This was likely due to higher frequency of anti-inflammatory microglia/macrophages, CD11b+CD206+ in infarcted tissue. Female mice also have decreased anti-inflammatory macrophages and IFNγ expression after MCAO
Bodhankar et al. [191]	Wild-type C57BL/6 J	10–12 weeks	Treatment with rIL-10 B cells inhibited proinflammatory cytokine production and differentiation into M2 microglia in both sexes. However, the inhibition was more pronounced in female mice. rIL-10 B cells also increase the production of the neuroprotectant IL-4 in females. Post-stroke, female mice have higher expression of IL-10R and IL-4Rα
Crain et al. [135]	C57Bl/6 mice	P3, P21,7–8 week, 4 months, 12 months	Microglia gene expression changes with age. The expression of inflammatory and anti-inflammatory cytokines is also sex dependent. Female mice had a more anti-inflammatory response at different age groups, but there was shift towards a more inflammatory phenotype in older mice
McCullough et al. [140]	C57BL/6 J XYM and wild-type C57BL/6 J mice bred to produce the following genotypes: XYM, XXM, XYF, XXF	18–20 months	Aged mice with a second X chromosome (XXF and XXM) had larger strokes volumes, with significantly more activated microglia and higher levels of inflammatory cytokines, when gonadal hormones are not present
Qi et al. [141]	C57BL/6 J XYM and wild-type C57BL/6 J mice bred to produce the following genotypes: XYM, XXM, XYF, XXF	18–22 months	The KDM-Histone-IRF pathway, which regulates microglia cytokine production, was more highly expressed in wild-type females and in FCG mice with 2 X chromosomes
Manwani et al. [193]	C57BL/6 mice	5–6 months, 14–15 months, and 20–22 months	Stroke leads to splenic contraction in male mice of all ages and aged female mice. Dendritic cells were recruited in higher numbers to the female compared to the male brain. No differences in the number of macrophages and neutrophils were identified
Dotson et al. [74]	C57BL/6 J mice	Not reported	Prior to splenectomy, male mice had larger stroke volumes than female mice. After splenectomy, male mice had reduced stroke volume such that there was no longer a difference in the infarct size between male and female mice. Activated microglia were reduced in females regardless of splenectomy and in males after splenectomy when compared to male mice without splenectomy
Morrison et al. [147]	C56BL6/J and C57BL/6 with CX3CR1GFP/+	3 months	Female mice have a higher number of CD11b microglia at baseline, whereas these numbers increase in males after MCAO. Astrocyte AQP4 changes polarity in male mice
Banerjee et al. [76]	C57BL/6 J mice	Not reported	Post-stroke, male mice have higher numbers of CD45hiCD11b+ microglial cells and macrophages
Villapol et al. [194]	C57BL6/J mice	Postnatal day 9	Male mice had more proinflammatory microglia markers in the ischemic brain compared to female mice, 3 days after stroke. Higher levels of the proinflammatory cytokine, TNF α, was seen in male mice
CordeauJr et al. ([195]	Transgenic GFAP-luc mice	10–17 week	Astrocyte response (GFAP upregulation) results in increased infarct size in males but not females

KO knock out, IL interleukin, MCAO middle cerebral artery occlusion, IFN interferon, FCG four core genotype, AQP aquaporin, TNF tissue necrosis factor, GFAP glial fibrillary acidic protein