Early Postnatal Intermittent Hypoxia Increases Rat Microglial Anti‐inflammatory Gene expression, Effects that Are Sex‐specific and Last into Adulthood

Abstract

Chronic intermittent hypoxia (IH), a hallmark of sleep‐disordered breathing (SDB), is prevalent in pediatric and pre‐term infant populations, and is often comorbid with infection. IH increases reactive oxygen species formation, causes neuronal apoptosis, promotes peripheral and CNS inflammation, and results in long‐term neurocognitive deficits in males. However, in the developing brain, little is known about how IH impacts the acute or long‐term inflammatory activities of microglia (CNS resident innate immune cells), or whether these responses differ by sex. Since inflammation impacts cognitive development, we tested the hypothesis that early life IH exposure will sex‐dependently alter microglial inflammatory gene responses and that these effects would last into adulthood. We exposed rat pups to 8 nights of IH beginning on the first postnatal day (P1) and assessed microglial responses to a peripheral lipopolysaccharide (LPS 1mg/kg, 3 hrs) challenge either the day after the last IH exposure (P9), or 6 weeks later (adult). Using RNA sequencing and qRT‐PCR, we first found that IH increased basal expression levels of the anti‐inflammatory cytokines interleukin‐4 (IL‐4) and interferon‐beta (IFNβ) in P9 microglia of both sexes. As expected, LPS‐stimulated inflammatory cytokine expression was decreased after postnatal IH, suggesting that IH may acutely skew neonatal microglia of both sexes towards an anti‐inflammatory phenotype. At P9, there were also sexual dimorphisms in non‐inflammatory microglial genes, both in basal and LPS‐stimulated conditions. For example, multiple genes involved in impaired cognition were upregulated in male microglia, potentially playing a role in the SDB‐induced cognitive impairments that are more prominent in males. Motif analyses to detect the transcription factors that may be driving these male‐specific differences in cognitive genes surprisingly identified the androgen receptor as the top transcriptional driver. Lastly, in adults exposed to neonatal IH, enhanced basal anti‐inflammatory cytokine gene expression was evident only in male microglia, even though their inflammatory gene responses to LPS did not appear to differ at this later time. Ongoing studies are investigating the consequences of persistent increases in anti‐inflammatory cytokines in male microglia on cognitive outcomes since they are known to alter neuroplasticity.Support or Funding InformationSupported by NIH R01 NS085226 and F31 NS100229This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.