Chronic Intermittent Hypoxia Exerts CNS Region-Specific Effects on Rat Microglial Inflammatory and TLR4 Gene Expression

Abstract

Intermittent hypoxia (IH) during sleep is a hallmark of sleep apnea, causing significant neuronal apoptosis, and cognitive and behavioral deficits in CNS regions underlying memory processing and executive functions. IH-induced neuroinflammation is thought to contribute to cognitive deficits after IH. In the present studies, we tested the hypothesis that IH would differentially induce inflammatory factor gene expression in microglia in a CNS region-dependent manner, and that the effects of IH would differ temporally. To test this hypothesis, adult rats were exposed to intermittent hypoxia (2 min intervals of 10.5% O2) for 8 hours/day during their respective sleep cycles for 1, 3 or 14 days. Cortex, medulla and spinal cord tissues were dissected, microglia were immunomagnetically isolated and mRNA levels of the inflammatory genes iNOS, COX-2, TNFα, IL-1β and IL-6 and the innate immune receptor TLR4 were compared to levels in normoxia. Inflammatory gene expression was also assessed in tissue homogenates (containing all CNS cells). We found that microglia from different CNS regions responded to IH differently. Cortical microglia had longer lasting inflammatory gene expression whereas spinal microglial gene expression was rapid and transient. We also observed that inflammatory gene expression in microglia frequently differed from that in tissue homogenates from the same region, indicating that cells other than microglia also contribute to IH-induced neuroinflammation. Lastly, microglial TLR4 mRNA levels were strongly upregulated by IH in a region- and time-dependent manner, and the increase in TLR4 expression appeared to coincide with timing of peak inflammatory gene expression, suggesting that TLR4 may play a role in IH-induced neuroinflammation. Together, these data indicate that microglial-specific neuroinflammation may play distinct roles in the effects of intermittent hypoxia in different CNS regions.

The impact of inflammation on respiratory plasticity

“…These differences may be due to the magnitude of inflammatory signaling or increased expression of trophic factors known to stimulate respiratory plasticity. For example, while one or three nights of IH induces inflammatory gene expression in spinal microglia (Huxtable et al, 2015; Smith et al, 2013), inflammatory gene expression in the spinal cord is not elevated after 14 consecutive nights of IH or after 4 weeks of thrice weekly IH (Peters et al, 2015; Smith et al, 2013). …”

“…One night of intermittent hypoxia (IH-1) abolishes pLTF (Huxtable et al, 2015), but seven days of intermittent hypoxia enhances pLTF (Ling et al, 2001). Such differing results may be explained by changes in inflammatory and neurotrophic signaling during repetitive hypoxic episodes (Huxtable et al, 2015; Peters et al, 2015; Smith et al, 2013). Additionally, treatment with anti-inflammatories blunts ventilatory acclimatization to CSH in humans (Basaran et al, 2016), but during CIH does not inhibit hypoxic sensitization (Del Rio et al, 2012; Iturriaga et al, 2015), suggesting the role of inflammation in CSH and CIH are distinct.…”

Inflammation in sleep apnea: An update

“…A recent study exposed rats to two weeks of IH and examined expression of inflammatory genes (iNOS, TNF-α, IL-1b, COX-2, IL-6) in the microglia of the cortex, medulla, and spinal cord at several time points[125]. Dynamic changes in transcription occurred, with most inflammatory markers increasing over time.…”

Human intermittent hypoxia-induced respiratory plasticity is not caused by inflammation

“…Between the two IH paradigms, the profile of the inflammatory response probably differs, with longer duration IH exposures being required to stimulate inflammation [26,43]. Therefore, IH-induced inflammation may be mechanistically more important in ventilatory changes following chronic IH, whereas IH-induced oxidative stress [8] and/or alterations in gaseous mediators of hypoxia sensing within the carotid bodies (e.g.…”