Abstract
BackgroundChronic obstructive pulmonary disease (COPD) remains a prevalent chronic airway inflammatory disease. Circular RNAs (circRNAs) are associated with inflammation regulation; therefore, we examined distinct effects of circRNA FOXO3 (circFOXO3) against pneumonic inflammatory processes in COPD.MethodsWe first quantified and localized circFOXO3 in mouse lung epithelial cell line MLE12 by quantitative reverse-transcription PCR and in situ hybridization. Next, circFOXO3 was suppressed by therapeutic administration of circFOXO3 knockdown lentivirus in mice exposed to air or cigarette smoke (CS) for 12 weeks, and several hallmarks of COPD were evaluated.ResultsWe noticed that circFOXO3 is upregulated in CS-exposed lungs and cigarette smoke extract (CSE)-treated murine alveolar epithelial cells. Knockdown of circFOXO3 attenuated the release of CXCL1 and IL-6 as well as inflammatory processes in the lungs of CS-exposed mice. In addition, we identified miR-214-3p as a circFOXO3-targeted microRNA. MiR-214-3p overexpression exerted protective effects against pneumonic inflammation after CS exposure. Silencing of circFOXO3 downregulated IKK-β mRNA (miR-214-3p’s target), resulting in the dysfunction of the NF-κB signaling pathway and attenuation of CSE-induced inflammatory-cytokine expression.ConclusionsCollectively, these findings reveal a crucial function of circFOXO3 in the pathological remodeling related to CS-induced inflammatory processes. Hence, circFOXO3 might be a good target for the treatment of inflammatory disorders similar to CS-induced lung inflammation.
Highlights
Chronic obstructive pulmonary disease (COPD) remains a prevalent chronic airway inflammatory disease
Certain dysregulated circRNAs may partake in the cellular airway response to cigarette smoke (CS)-provoked stress, offering various justifications for testing circRNA involvement in COPD [6]
CircFOXO3 expression is increased in lung parenchyma of a mouse model and MLE12 cells after CS treatment We first explored the effects of CS on circFOXO3 levels in mouse lungs
Summary
Chronic obstructive pulmonary disease (COPD) remains a prevalent chronic airway inflammatory disease. Circular RNAs (circRNAs) are associated with inflammation regulation; we examined distinct effects of circRNA FOXO3 (circFOXO3) against pneumonic inflammatory processes in COPD. Alterations of circRNA expression levels may correlate with the pathophysiology of individual diseases, e.g., pulmonary and airway diseases, such as COPD. Zeng and colleagues have performed RNA sequencing and found unusual circRNA expression patterns in central HSAECs exposed to a cigarette smoke extract (CSE). Certain dysregulated circRNAs may partake in the cellular airway response to cigarette smoke (CS)-provoked stress, offering various justifications for testing circRNA involvement in COPD [6]. Qiao et al have demonstrated that a circ-RBMS1 knockdown mitigates CSE-induced apoptosis, oxidative stress, and lung inflammatory processes by upregulating FBXO11 or via miR-197-3p in 16HBE cells [7]. Despite circFOXO3’s practical importance, its possible participation in the regulation of CS-induced inflammatory responses is still poorly studied
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