IL-33/ST2 mediating systemic inflammation and neuroinflammation through NF-kB participated in the neurocognitive impairment in obstructive sleep apnea.

Abstract

Increasing evidence has noted that neuroinflammation contributes to the pathological processes of cognitive impairment of obstructive sleep apnea (OSA) patients. Interleukin (IL) -33/suppression of tumorigenicity 2 (ST2) signaling pathway plays well-defined roles in the inflammatory progression. The study aims to elucidate whether IL-33/ST2 signaling pathway plays a role in the cognitive dysfunction in patients with OSA via regulating neuroinflammation. We found that compared with control subjects, patients with OSA showed significantly elevated IL-33, ST2 and p65 nuclear factor-kappa B (NF-κB) levels in peripheral blood mononuclear cells (PBMCs) and inflammatory cytokines IL-6, IL-8 in serum, which were positively correlated with disease severity. Meanwhile, OSA patients exhibited a decline in Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores, suggesting mild cognitive impairment. Continuous positive airway pressure (CPAP) treatment for 12weeks significantly decreased the expression of IL-33, ST2, p65NF-κB, IL-6 and IL-8, as well as improved cognitive function of OSA patients. Moreover, the IL-33/ST2 signaling was closely correlated with sleep respiratory parameters and cognitive dysfunction. To further explore the underlying mechanism of IL-33/ST2 signaling pathway, we stimulated human microglial clone 3 (HMC3) cells with lipopolysaccharide (LPS) to mimic neuroinflammatory response in vitro. The results showed that LPS treatment led to an increase in IL-33 and ST2 expression in a dose- dependent manner, along with an increased secretion of IL-6 and IL-8. Functional experiments showed that knockdown of IL-33 ameliorated LPS-induced neuroinflammation via suppressing NF-κB signaling. Overall, current findings suggest that IL-33/ST2 signaling participated in the cognitive impairment of OSA patients by promoting neuroinflammation via activating NF-κB signaling. These results may provide a novel therapeutic target for treating OSA- associated cognitive dysfunction.