Sex‐Specific Alterations in LPS‐Induced Peripheral and Central Inflammation in Adult Offspring Exposed to Gestational Intermittent Hypoxia: Potential Regulation by miR‐146

Abstract

The prevalence of obstructive sleep apnea (OSA) and concomitant intermittent hypoxia (IH) in pregnant women is rising in parallel with the obesity epidemic. IH causes profound inflammation, and it is well‐established that maternal immune activation can lead to detrimental outcomes in her offspring. Although in recent years the acute consequences of maternal OSA on the health of both the mother and the newborn have become better appreciated, little remains known about the potential long‐lasting consequences to the offspring in adulthood. Given the effect of inflammation on the neural control of breathing, we studied the consequences of gestational intermittent hypoxia (GIH) on the central and peripheral immune responses of adult male and female offspring. We exposed rat dams to IH from gestational days 10–21 (8hrs/day, 2 min cycles alternating between 10.5% O2 and 21%O2, mimicking the desaturation and resaturation kinetics of human OSA). We challenged the adult offspring with a peripheral LPS injection (1 mg/kg i.p., 3 hrs) and assessed neural (whole brain homogenates) and peripheral (spleen) cytokine gene expression. We found that GIH gene‐specifically enhanced LPS‐induced neuroinflammation in adult offspring of both sexes. Conversely, while LPS‐induced peripheral inflammation was unchanged in GIH male offspring, it was strongly attenuated in GIH females, suggesting that the central and peripheral immune responses are differentially impacted by GIH, and that these effects differ by sex. Because microRNAs (miRNAs) are critical regulators of the immune response, we tested the hypothesis that miRNAs are differentially expressed in male and female GIH offspring. In spleens from adult GIH offspring, we screened the levels of several immunoregulatory miRNAs. Interestingly, miR‐146, a strongly immunosuppressive miRNA, was highly upregulated in female spleens. We suggest that augmented miR‐146 levels suppress peripheral immune responses to an inflammatory challenge in GIH offspring, and that miR‐146 levels will be reduced in the brain where neuroinflammation is enhanced in GIH offspring. Studies are underway using lentiviral‐mediated manipulation of miR‐146 activity to more directly test this hypothesis, and to understand how central and peripheral inflammation are ultimately regulated in the context of GIH. Regulating miR‐146 expression in adults exposed to maternal OSA in utero may represent a novel therapeutic target to control the detrimental consequences of aberrant inflammatory signaling.Support or Funding InformationSupported by NIH R01 NS085226 and HL105511, and a Wisconsin Alumni Research Foundation UW2020 grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.