miR-21-5p Under-Expression in Patients with Obstructive Sleep Apnea Modulates Intermittent Hypoxia with Re-Oxygenation-Induced-Cell Apoptosis and Cytotoxicity by Targeting Pro-Inflammatory TNF-α-TLR4 Signaling

Abstract

The purpose of this study is to explore the anti-inflammatory role of microRNAs (miR)-21 and miR-23 targeting the TLR/TNF-α pathway in response to chronic intermittent hypoxia with re-oxygenation (IHR) injury in patients with obstructive sleep apnea (OSA). Gene expression levels of the miR-21/23a, and their predicted target genes were assessed in peripheral blood mononuclear cells from 40 treatment-naive severe OSA patients, and 20 matched subjects with primary snoring (PS). Human monocytic THP-1 cell lines were induced to undergo apoptosis under IHR exposures, and transfected with miR-21-5p mimic. Both miR-21-5p and miR-23-3p gene expressions were decreased in OSA patients as compared with that in PS subjects, while TNF-α gene expression was increased. Both miR-21-5p and miR-23-3p gene expressions were negatively correlated with apnea hypopnea index and oxygen desaturation index, while TNF-α gene expression positively correlated with apnea hypopnea index. In vitro IHR treatment resulted in decreased miR-21-5p and miR-23-3p expressions. Apoptosis, cytotoxicity, and gene expressions of their predicted target genes-including TNF-α, ELF2, NFAT5, HIF-2α, IL6, IL6R, EDNRB, and TLR4-were all increased in response to IHR, while all were reversed with miR-21-5p mimic transfection under IHR condition. The findings provide biological insight into mechanisms by which IHR-suppressed miRs protect cell apoptosis via inhibit inflammation, and indicate that over-expression of the miR-21-5p may be a new therapy for OSA.

lncRNA GAS5‑mediated miR‑23a‑3p promotes inflammation and cell apoptosis by targeting TLR4 in a cell model of sepsis

“…In another study, miR-23a-3p was reported to inhibit monocyte function and phagocytosis by targeting TLR4/TNF-α/TGF-β1/IL-10 signaling in patients with active tuberculosis with a high bacterial load via interferon regulatory factor 1/transcription factor SP1 ( 26 ). In addition, the downregulation of miR-21-5p in patients with obstructive sleep apnea has been shown to regulate intermittent hypoxia and reoxygenation-induced apoptosis and cytotoxicity by targeting pro-inflammatory TNF-α/TLR4 signaling ( 27 ). In the present study, TLR4 was identified as a gene that is directly targeted by miR-23a-3p, and a clear negative association between miR-23a-3p and TLR4 expression was observed.…”

MicroRNA in extracellular vesicles regulates inflammation through macrophages under hypoxia

“…Moreover, miR-21 plays a part in anti-inflammatory and anti-apoptosis by inhibiting NF-κB-TNF-α-TLR and PDCD4/caspase-3 pathway, respectively [ 80 , 81 ]. Chen et al confirmed that miR-21-5p protects monocytes in chronic intermittent hypoxia re-oxygenation by inhibiting the expression of inflammation-related genes [ 82 ]. Besides, the secretion of inflammatory cytokines (such as IL-6, IL-1β, TNF-α) and chemokine receptor7 also can be inhibited by miR-21 under hypoxia.…”

Roles of Exosomes and Exosomal MicroRNAs in Postoperative Sleep Disturbance

“… 118 In mice, MSC-derived exosomes significantly increased miR-21 levels after hypoxic preconditioning, resulting in downregulation of signal transducer and activator of transcription 3 phosphorylation and inhibition of NF-kB activation, which reduced the neuroinflammatory response in the brain. 94 Additionally, other studies reported that miR-21 levels are related to attenuated inflammatory responses, and that reduced miR-206 expression via exosome delivery upregulates BDNF/tropomyosin receptor kinase B/CREB signalling, which exerts a neuroprotective effect on subarachnoid haemorrhage. 103 Exosomes are naturally produced by human cells.…”

“…93 In addition to miR-155 and miR-146a, miR-21, miR-23, miR-224-5p, and miR-181c regulate proteins involved in the TLR signalling pathway. [94][95][96] TRIM2, a target of miR-181c, reduces the ubiquitination of nerve-fibre filaments (neurofilament light), and promotes neuronal remodelling in the hippocampus exposed to hypoxia. 96 Although activation of the inflammatory pathway is clearly an important factor in the development of cognitive impairment, additional research is needed to identify a direct link.…”