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. 2021 Sep;25(3):1641-1653.
doi: 10.1007/s11325-020-02205-y. Epub 2020 Oct 9.

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

Ye Wang  1 , Richard B Meagher  2 , Suresh Ambati  3 , Ping Ma  1 , Bradley G Phillips  4   5
Affiliations

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

Ye Wang et al. Sleep Breath. 2021 Sep.

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.

Keywords: Airways therapy; CPAP; Cytokines; Microglia; Neurodegenerative disease; OSA; Obstructive sleep apnea.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
The levels of four cytokine receptors involved in neurodegenerative disease risk are low in OSA patients, but their levels in airway-treated OSA patients are indistinguishable from those in control subjects. The serum picogram per milliliter (pg/mL) levels of the soluble isoforms of a gp130, b IL6R, c TNFR1, and c TNFR2 for the eight control individuals, nineteen airway-treated apneic patients, and nineteen apneic patients not receiving airways therapy are summarized in box blots. The boxed area encloses the second and third quartile and is bounded by median pg/mL value indicated by a black line. The lower and upper whiskered ranges indicate the first quartile-1.5*IQR (interquartile range) and the third quintile +1.5*IQR, respectively. Each of the three independent Bio-Plex estimates of a cytokine level for each patient is represented by separate data points. Potential outlying data among airways treated patients are encircled by a red dotted line
Fig. 2
Fig. 2
t-SNE clustered the cytokine receptor data for all OSA and airway-treated OSA patients and control individuals into two groups. Cluster 1 represents the dimensional distribution and grouping of data for four cytokines for all the control individuals, fifteen of the nineteen airway-treated OSA patients, and one untreated OSA patient. Cluster 2 represents the dimensional distribution of cytokine data among all but one of the untreated OSA patients and five of the airway-treated OSA patients. Each patient is represented by three separate data points. The individual patient numbers for the airway-treated OSA patient data are indicated in each cluster
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