Live imaging of neuroinflammation reveals sex and estrogen effects on astrocyte response to ischemic injury.
OBJECTIVE
We sought to develop a model system for live analysis of brain inflammatory response in ischemic injury.


METHODS
Using a reporter mouse-expressing luciferase gene under transcriptional control of the murine glial fibrillary acidic protein (GFAP) promoter (GFAP-luc mice) and biophotonic/bioluminescent imaging as tools, we developed a model system for in vivo analysis of astrocyte activation/response in cerebral ischemia.


RESULTS
Analysis of photon emissions from the brains of living animals revealed marked sex differences in astrocyte response to ischemic injury. The increase in GFAP signals was significantly higher in female mice in the metestrus/diestrus period compared with male transgenic mice (1.71 x 10(7)+/-0.19 x 10(7) vs 0.92 x 10(7)+/-0.15 x 10(7), P<0.001). Similar results were obtained by quantitative immunohistochemistry (males vs females: 13.4+/-0.5 vs 16.96+/-0.64, P<0.0001). However, astrocyte activation/GFAP signals showed cyclic, estrus-dependent variations in response to ischemic injury. Physiologically higher levels of estrogen and application of pharmacologic doses of estrogen during replacement therapy attenuated GFAP upregulation after stroke. Interestingly, contrary to a positive correlation between the intensities of GFAP signals and infarct size in male mice, no such correlation was observed in any of the experimental groups of female GFAP-luc mice.


CONCLUSIONS
Our results suggest that GFAP upregulation in ischemic injury may have different functional significance in female and male experimental animals and may not directly reflect the extent of ischemia-induced neuronal damage in female GFAP-luc mice. Using a novel live imaging approach, we demonstrated that the early-phase brain inflammatory response to ischemia may be associated with sex-specific biomarkers of brain damage.
Cordeau
Pierre
P
Department of Anatomy and Physiology, Université Laval, Québec, Canada.
Lalancette-Hébert
Mélanie
M
Weng
Yuan Cheng
YC
Kriz
Jasna
J
D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology; D004031:Diestrus; D004660:Encephalitis / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D049449:Luminescence; D008297:Male; D008686:Metestrus; D051379:Mice; D008822:Mice, Transgenic; D012737:Sex Factors; D015854:Up-Regulation / Q000187:drug effects
D004967:Estrogens; D005904:Glial Fibrillary Acidic Protein