Sex, stroke, and inflammation: the potential for estrogen-mediated immunoprotection in stroke

Abstract

Stroke is the third leading cause of death and the primary cause of disability in the developed world. Experimental and clinical data indicate that stroke is a sexually dimorphic disease, with males demonstrating an enhanced intrinsic sensitivity to ischemic damage throughout most of their lifespan. The neuroprotective role of estrogen in the female brain is well established, however, estrogen exposure can also be deleterious, especially in older women. The mechanisms for this remain unclear. Our current understanding is based on studies examining estrogen as it relates to neuronal injury, yet cerebral ischemia also induces a robust sterile inflammatory response involving local and systemic immune cells. Despite the potent anti-inflammatory effects of estrogen, few studies have investigated the contribution of estrogen to sex differences in the inflammatory response to stroke. This review examines the potential role for estrogen-mediated immunoprotection in ischemic injury.

Figure 1. The potential estrogenic effects on glial cells in the ischemic brain

The anti-inflammatory effects of estrogen in the brain are primarily mediated by glial cells. Estrogen promotes a resting phenotype in microglia, as evidenced by increased ramified morphology and decreased MHCII expression. These actions serve to limit microglial activation, proliferation, and migration toward the injured site. Similar changes occur in astrocytes, ultimately leading to decreased glial scar formation. Estrogen-mediated decrease in aquaporin expression prevents osmotic imbalance and may lower risk of edema. Pro-inflammatory cytokines and chemoattractant signals normally released by activated astrocytes and microglia are suppressed in the presence of estrogen, thereby reducing extravasation of infiltrating immune cells. As well, estrogen enhances astrocytic expression of glutamate transporters which facilitates glutamate uptake, mitigating injury due to neuronal excitoxicity. In addition, astrocytes increase synthesis of endogenous steroid production after injury, and secrete growth factors like VEGF, which promote angiogenesis. Together, these actions have a profound impact on curbing neuronal injury due to ischemia by conferring protection via local immunosuppression. The green arrow represents enhancing or promoting action, and the red arrow represents inhibitory action. Abbreviations: E2 (17 beta-estradiol), MHCII (major histocompatibility complex class II), VEGF (vascular endothelial growth factor)

Figure 2. Microglial activation after stroke

Coronal section of mouse brain at low (10×) and high (20×) power demonstrating increased Iba staining (a marker for microglia) in the penumbral region (indicated by a box in the schematic section) in ovariectomized females both at baseline (sham) and after stroke. DAPI was utilized as a nuclear counter stain.

Figure 3. The atheroprotective effects of estrogen

Primary and secondary stroke prevention centers around vascular dysfunction associated with atherosclerosis and blood clotting, respectively. Macrophages are key players in atherogenesis, the development of arterial plaques. Estrogen acts to suppress pro-inflammatory cytokine production, and enhance removal of dead cells from the atherosclerotic tissue. Decreased uptake of modified lipoproteins prevents foam cell formation. Estrogen also prevents lipid buildup by increasing cholesterol ester metabolism and enhancing efflux transport of cholesterol out of the cell. Excessive blood clotting in response to vascular injury following stroke can impede reperfusion of blood flow back to ischemic tissue. Platelets are major contributors in the formation of blood clots. Estrogen has been shown to increase platelet- and endothelial derived NO levels, which plays an important role in reducing adhesion, aggregation, and recruitment. Decreased platelet-leukocyte aggregation due to estrogen exposure prevents lesion progression, plaque rupture, thrombus formation, and the risk of embolization. In sum, these changes prevent clotting and re-establish blood flow back to the ischemic site. The green arrow represents enhancing or promoting action. Abbreviations: Ox-LDL (oxidized low-density lipoprotein), NO (nitric oxide), ATP (adenosine triphosphate)