Abstract
Intermittent Hypoxia (IH), a hallmark of sleep apnea, causes severe neurologic deficits. Inflammation underlies much IH‐induced neuropathology, including cortical/hippocampal neuronal apoptosis and obliteration of phrenic long‐term facilitation, a form of spinal respiratory motor plasticity. We tested the idea that microglial responses to IH differ by CNS region and that the presence of soluble, IH‐induced toll‐like receptor 4 (TLR4) ligands play a role. Animals were treated with 8–12hrs of IH or normoxia for 1–14 days. Various CNS regions were harvested, dissociated, and pelleted for immunomagnetic isolation of microglia. Soluble IH‐induced factors remained in the sample supernatants. Microglial activation was assessed by flow cytometry and/or qRT‐PCR and was found to differ by CNS region. To investigate the mechanism whereby IH activates microglia, we treated microglial cultures with CNS supernatants. The soluble factors from IH‐treated animals induced activation of cultured microglia, pro‐inflammatory effects that were absent in microglia with nonfunctional TLR4. These data suggest that endogenous molecule(s) released during IH may signal through TLR4 to promote microglial activation and neuroinflammation in vivo. This is the first study to demonstrate regional differences in microglial inflammatory responses to IH, and to investigate their mechanistic underpinnings.
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