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

Dandan-Zong; Chong Shen; Xiangming Liu; Ting Liu; Yanru Ou; Ruoyun Ouyang

doi:10.1016/j.intimp.2022.109604

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

Int Immunopharmacol. 2023 Feb:115:109604. doi: 10.1016/j.intimp.2022.109604. Epub 2022 Dec 27.

Authors

Dandan-Zong¹, Chong Shen¹, Xiangming Liu¹, Ting Liu¹, Yanru Ou¹, Ruoyun Ouyang²

Affiliations

¹ Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China.
² Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China; Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan 410011, China. Electronic address: [email protected].

PMID: 36580760
DOI: 10.1016/j.intimp.2022.109604

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 12 weeks 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.

Keywords: CPAP; Cognitive impairment; IL-33/ST2 signaling pathway; Inflammation; NF-κB signaling; Obstructive sleep apnea.

MeSH terms

Humans
Inflammation / drug therapy
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Interleukin-6 / therapeutic use
Interleukin-8 / therapeutic use
Leukocytes, Mononuclear / metabolism
Lipopolysaccharides / therapeutic use
NF-kappa B* / metabolism
Neuroinflammatory Diseases
Sleep Apnea, Obstructive*

Substances

Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Interleukin-6
Interleukin-8
Lipopolysaccharides
NF-kappa B
IL33 protein, human
IL1RL1 protein, human