Sex Differences in Microglial Responses to Chronic Intermittent Hypoxia

Abstract

Chronic intermittent hypoxia is a hallmark of obstructive sleep apnea (OSA) that causes neuroinflammation and impairs one form of respiratory motor plasticity, phrenic nerve long‐term facilitation (pLTF). Interestingly, the prevalence of OSA is lower in women than in men, although this difference greatly decreases after menopause, suggesting that ovarian hormones may play a protective role. Although estrogen is well known to be anti‐inflammatory following ischemic/hypoxic injury, little is known about its ability to control neuroinflammation as it impacts respiratory neuroplasticity, or in response to inflammation induced by aspects of sleep disordered breathing. Our pilot data suggest that compared to males, microglia (CNS resident immune cells) from females display reduced inflammatory activities as evidenced by reduced cytokine expression (interleukins (IL)‐1b and ‐6), and decreased upregulation of surface CD14 levels. We evaluated differences in estrogen receptor alpha (ERa) expression in male and female microglia because ERa is well‐known to mediate anti‐inflammatory effects of estrogen in the CNS. Although we found no detectable differences in basal ERa expression, we did find that CIH reduced ERa in male microglia, but not in female. These preliminary observations suggest that males may not receive the same benefit of ERa‐mediated anti‐inflammatory activities that females do. Current studies are aimed at understanding the role of gonadal estrogen in creating these sexual dimorphisms in microglial neuroinflammatory responses to CIH. Results from this work will provide significant insight into mechanisms that can be exploited to minimize destabilization of respiratory plasticity in both sexes. (Supported by NIH R01 HL111598).