Sexually dimorphic microglia and ischemic stroke

Kerr, Nadine; Dietrich, Dalton W.; Bramlett, Helen M.; Raval, Ami P.

doi:10.1111/cns.13267

Cited by 72 publications

(70 citation statements)

References 107 publications

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“…There have been several reports regarding sex-and region-specific effects following HI insult from the perspective of mitochondrial metabolism and apoptotic mechanism [55][56][57]. Further, there have been previous reports on sex differences in the microglia number and function [40,58]. These overall differences might contribute toward TUNEL staining differences.…”

Section: Discussionmentioning

confidence: 98%

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice

Tsuji

Martino

Mukai

et al. 2020

J Neuroinflammation

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Background: Neuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE). Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states. However, the effects of microglial depletion on neonatal HIE remain unclear. Methods: Tamoxifen was administered to Cx3cr1 CreER/+ Rosa26 DTA/+ (microglia-depleted model) and Cx3cr1 CreER/+ Rosa26 DTA/− (control) mice at P8 and P9 to assess the effect of microglial depletion. The density of microglia was quantified using Iba-1 staining. Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis. At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10. The infarct size and apoptotic cells were analyzed at P13. Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13.Results: At P10, tamoxifen administration induced > 99% microglial depletion in DTA + mice. Following HI insult, there was persisted microglial depletion over 97% at P13. Compared to male DTA − mice, male DTA + mice exhibited significantly larger infarct volumes; however, there were no significant differences among females. Moreover, compared to male DTA − mice, male DTA + mice had a significantly higher density of TUNEL + cells in the caudoputamen, cerebral cortex, and thalamus. Moreover, compared to female DTA − mice, female DTA + mice showed a significantly greater number of TUNEL + cells in the hippocampus and thalamus. Compared to DTA − mice, ELISA revealed significantly lower IL-10 and TGF-β levels in both male and female DTA + mice under both normal conditions and after HI (more pronounced). Conclusion: We established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males.

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Section: Discussionmentioning

confidence: 98%

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice

Tsuji

Martino

Mukai

et al. 2020

J Neuroinflammation

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“…HUA is just one of many conditions that have observable sex differences, as differing pathologies based on sex have been observed in a variety of fields [14][15][16][17] including cardiovascular [18][19][20][21], neurological [22][23][24][25], immunological [26][27][28], and renal diseases [29][30][31][32][33]. The architecture of the female kidney is likely distinct from that of the male kidney [34], given women have a lower blood pressure than men [35], women are less likely to develop acute kidney injury than men [36,37], women demonstrate improved tolerance to renal ischemia [38,39], and women are protected from renal and cardiovascular disease before menopause as compared to men [40,41].…”

Section: Urate As a Risk Factor In Diseasementioning

confidence: 99%

Sex Differences in Urate Handling

Kuhns

Woodward

2020

IJMS

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Hyperuricemia, or elevated serum urate, causes urate kidney stones and gout and also increases the incidence of many other conditions including renal disease, cardiovascular disease, and metabolic syndrome. As we gain mechanistic insight into how urate contributes to human disease, a clear sex difference has emerged in the physiological regulation of urate homeostasis. This review summarizes our current understanding of urate as a disease risk factor and how being of the female sex appears protective. Further, we review the mechanisms of renal handling of urate and the significant contributions from powerful genome-wide association studies of serum urate. We also explore the role of sex in the regulation of specific renal urate transporters and the power of new animal models of hyperuricemia to inform on the role of sex and hyperuricemia in disease pathogenesis. Finally, we advocate the use of sex differences in urate handling as a potent tool in gaining a further understanding of physiological regulation of urate homeostasis and for presenting new avenues for treating the constellation of urate related pathologies.

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“…There have been several reports regarding sex-and regionspecific effects following HI insult from the perspective of mitochondrial metabolism and apoptotic mechanism [55][56][57]. Further, there have been previous reports on sex differences in the microglia number and function [40,58]. These overall differences might contribute toward TUNEL staining differences.…”

Section: Discussionmentioning

confidence: 98%

Aggravated brain injury after neonatal hypoxic ischemia in microglia depleted mice

Tsuji

Martino

Mukai

et al. 2020

Preprint

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Background: Neuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE). Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states. However, the effects of microglial depletion on neonatal HIE remain unclear. Methods: Tamoxifen was administered to Cx3cr1 CreER/+ Rosa26 DTA/+ (microglia-depleted model) and Cx3cr1 CreER/+ Rosa26 DTA/- (control) mice at P8 and P9 to assess the effect of microglial depletion. The density of microglia was quantified using Iba-1 staining. Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis. At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10. The infarct size and apoptotic cells were analyzed at P13. Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13. Results: At P10, tamoxifen administration induced >99% microglial depletion in DTA + mice. Following HI insult, there was persisted microglial depletion over 97% at P13. Compared to male DTA - mice, male DTA + mice exhibited significantly larger infarct volumes; however, there were no significant differences among females. Moreover, compared to male DTA - mice, male DTA + mice had a significantly higher density of TUNEL + cells in the caudoputamen, cerebral cortex, and thalamus. Moreover, compared to female DTA - mice, female DTA + mice showed a significantly greater number of TUNEL + cells in the hippocampus and thalamus. Compared to DTA - mice, ELISA revealed significantly lower IL-10 and TGF-β levels in both male and female DTA + mice under both normal conditions and after HI (more pronounced). Conclusion: We established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males.

show abstract

Sexually dimorphic microglia and ischemic stroke

Cited by 72 publications

References 107 publications

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice

Sex Differences in Urate Handling

Aggravated brain injury after neonatal hypoxic ischemia in microglia depleted mice

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