Patients with obstructive sleep apnea have suppressed levels of soluble cytokine receptors involved in neurodegenerative disease, but normal levels with airways therapy

Abstract

Purpose Obstructive sleep apnea (OSA) results in systemic intermittent hypoxia. By one model, hypoxic stress signaling in OSA patients alters the levels of inflammatory soluble cytokines TNF and IL6, damages the blood brain barrier, and activates microglial targeting of neuronal cell death to increase the risk of neurodegenerative disorders and other diseases. However, it is not yet clear if OSA significantly alters the levels of the soluble isoforms of TNF receptors TNFR1 and TNFR2 and IL6 receptor (IL6R) and co-receptor gp130, which have the potential to modulate TNF and IL6 signaling. Methods Picogram per milliliter levels of the soluble isoforms of these four cytokine receptors were estimated in OSA patients, in OSA patients receiving airways therapy, and in healthy control subjects. Triplicate samples were examined using Bio-Plex fluorescent bead microfluidic technology. The statistical significance of cytokine data was estimated using the nonparametric Wilcoxon rank-sum test. The clustering of these high-dimensional data was visualized using t-distributed stochastic neighbor embedding (t-SNE). Results OSA patients had significant twofold to sevenfold reductions in the soluble serum isoforms of all four cytokine receptors, gp130, IL6R, TNFR1, and TNFR2, as compared with control individuals (p = 1.8 × 10−13 to 4 × 10−8). Relative to untreated OSA patients, airways therapy of OSA patients had significantly higher levels of gp130 (p = 2.8 × 10−13), IL6R (p = 1.1 × 10−9), TNFR1 (p = 2.5 × 10−10), and TNFR2 (p = 5.7 × 10−9), levels indistinguishable from controls (p = 0.29 to 0.95). The data for most airway-treated patients clustered with healthy controls, but the data for a few airway-treated patients clustered with apneic patients. Conclusions Patients with OSA have aberrantly low levels of four soluble cytokine receptors associated with neurodegenerative disease, gp130, IL6R, TNFR1, and TNFR2. Most OSA patients receiving airways therapy have receptor levels indistinguishable from healthy controls, suggesting a chronic intermittent hypoxia may be one of the factors contributing to low receptor levels in untreated OSA patients.

Cellular Immune Dysfunction in Obstructive Sleep Apnea

“…Both increased and decreased levels of reactive oxygen species (ROS) in neutrophil granulocytes have been reported ( 37 , 38 ). Similarly, there are both observations on NK, NKT, and B cells describing an increase and a decrease in the respective cell population ( 3 , 31 , 32 , 36 , 44 ). CD4 + effector T cells have been detected at increased levels in OSA patients ( 21 ).…”

“…An association between the depletion of myeloid and plasmatic dendritic cells was also demonstrated, which correlates with the already known assumption that IL-6 is an inhibitor for the maturation of dendritic cells ( 34 ). Chronically high levels of proinflammatory cytokines may induce neuroinflammation and/or neurodegeneration ( 49 ), which is interesting because OSA is suspected to have neurodegenerative features ( 44 , 50 ) and sleep disorders such as OSA occur or worsen in patients with neurodegenerative diseases, such as Parkinson's disease, Alzheimer disease or amyotrophic lateral sclerosis ( 51 – 53 ).…”

An Overview of the Obese-Asthma Phenotype in Children

“…OSA is associated with systemic inflammation, and in obese patients, the intermittent hypoxemia associated with repeated obstructive episodes may exacerbate already existing adipose tissue hypoxia, worsening adipocyte death, macrophage infiltration and consequent systemic inflammation [ 130 ]. There is evidence that continuous positive airway pressure (CPAP) may reduce systemic inflammation in obese asthmatics and also decrease airway responsiveness, asthma symptoms and SABA use [ 133 ]. Bariatric surgery improves both asthma and OSA [ 134 ].…”

Sex-dependent effects of chronic intermittent hypoxia: Implication for obstructive sleep apnea

“…Patients diagnosed with OSA are typically treated with continuous positive airway pressure (CPAP) machines, the gold standard for therapy [20][21][22]. Effective CPAP therapy can reduce in ammation, OS, and cognitive dysfunction [21,[23][24][25]. However, adherence to CPAP therapy is a major issue, as 15-40% of patients are non-compliant with prescribed machine usage [20][21][22].…”