Brines, M. | Search bioRxiv

bioRxiv2023

Increased plasma lipopolysaccharide-binding protein and altered inflammatory mediators in overweight women suggest a state of subclinical endotoxemia

Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-binding protein (LBP), CRP, IL-6, leptin, and adiponectin in adult female subjects (n=40) who were lean or overweight and had high cholesterol and/or high blood pressure - two important conventional risk factors for CVD. Plasma levels of LBP were significantly higher in the overweight group compared with the lean group (P=0.005). The levels of CRP were also significantly higher in overweight subjects (P=0.01), as were IL-6 (P=0.02) and leptin (P=0.002), pro-inflammatory mediators associated with cardiovascular risk. Levels of adiponectin, an adipokine with anti-inflammatory and anti- atherogenic functions, were significantly lower in the overweight group (P=0.002). The leptin/adiponectin ratio, a preferential atherogenic marker was significantly increased in women who are overweight (P=0.02). LBP, CRP, leptin, and adiponectin levels significantly correlated with BMI, but not with age and there was a significant correlation between LBP and IL-6 levels. These results reveal the presence of subclinical endotoxemia and a pro-inflammatory state in overweight women and are of interest for further studies with the goal for improved understanding of cardiovascular health risks in women.

immunology↗

bioRxiv2023

Electrical stimulation of the dorsal motor nucleus of the vagus regulates inflammation without affecting the heart rate

BackgroundThe vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN) as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications, but the anti-inflammatory efficacy of electrical DMN stimulation (eDMNS) was not previously investigated. Here, we examined the effects of eDMNS on heart rate (HR) and cytokine levels in murine endotoxemia as well as the cecal ligation and puncture (CLP) model of sepsis. MethodsAnesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (50, 250 or 500 A and 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 A or 50 A was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24h after CLP. CLP survival was monitored for 14 days. ResultsEither left or right eDMNS at 250 A and 500 A decreased HR, compared with pre- and post-stimulation. This effect was not observed at 50 A. Left side eDMNS at 50 A, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and were not associated with serum corticosterone alterations. Right side eDMNS suppressed serum TNF levels but had no effects on serum IL-10 and on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum TNF and IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice. ConclusionsFor the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation and these effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.

physiology↗