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MiR-4456/CCL3/CCR5 Pathway in the Pathogenesis of Tight Junction Impairment in Chronic Obstructive Pulmonary Disease.

ABSTRACT: Background: Cigarette smoke exposure (CSE) is a major cause of chronic obstructive pulmonary disease (COPD). The smoke disrupts cell-cell adhesion by inducing epithelial barrier damage to the tight junction (TJ) proteins. Even though the inflammatory mechanism of chemokine (C-C motif) ligand 3 (CCL3) in COPD has gained increasing attention in the research community, however, the underlying signaling pathway, remains unknown. Objectives: To identify the relationship of CCL3 in the pathogenesis of tight junction impairment in COPD and the pathway through which CSE causes damage to TJ in COPD via CCL3, both in vivo and in vitro. Methods: We screened the inflammatory factors in the peripheral blood mononuclear cells (PBMCs) from healthy controls and patients at each GOLD 1-4 stage of chronic obstructive pulmonary disease. RT-PCR, western blot, and ELISA were used to detect the levels of CCL3, ZO-1, and occludin after Cigarette smoke exposure. Immunofluorescence was applied to examine the impairment of the TJs in 16-HBE and A549 cells. The reverse assay was used to detect the effect of a CCR5 antagonist (DAPTA) in COPD. In the CSE-induced COPD mouse model, H&E staining and lung function tests were used to evaluate the pathological and physical states in each group. Immunofluorescence was used to assess the impairment of TJs in each group. ELISA and RT-PCR were used to examine the mRNA or protein expression of CCL3 or miR-4456 in each group. Results: The in vivo and in vitro results showed that CCL3 expression was increased in COPD compared with healthy controls. CCL3 caused significant injury to TJs through its C-C chemokine receptor type 5 (CCR5), while miR-4456 could suppress the effect of CCL3 on TJs by binding to the 3'-UTR of CCL3. Conclusion: miR-4456/CCL3/CCR5 pathway may be a potential target pathway for the treatment of COPD.

SUBMITTER: Yu W

PROVIDER: S-EPMC8089484 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsRecent studies have shown that cigarette smoke (CS)-induced oxidative stress impairs autophagy, resulting in aggresome-formation that correlates with severity of chronic obstructive pulmonary disease (COPD)-emphysema, although the specific step in autophagy pathway that is impaired is unknown. Hence, in this study, we aimed to evaluate the role of master autophagy transcription factor EB (TFEB) in CS-induced COPD-emphysema pathogenesis.ResultsWe first observed that TFEB accumulates in perinuclear spaces as aggresome-bodies in COPD lung tissues of tobacco smokers and severe emphysema subjects, compared with non-emphysema or nonsmoker controls. Next, Beas2b cells and C57BL/6 mice were exposed to either cigarette smoke extract (CSE) or subchronic-CS (sc-CS), followed by treatment with potent TFEB-inducing drug, gemfibrozil (GEM, or fisetin as an alternate), to experimentally verify the role of TFEB in COPD. Our in vitro results indicate that GEM/fisetin-mediated TFEB induction significantly (p?<?0.05) decreases CSE-induced autophagy-impairment (Ub/LC3B reporter and autophagy flux assay) and resulting aggresome-formation (Ub/p62 coexpression/accumulation; immunoblotting and staining) by controlling reactive oxygen species (ROS) activity. Intriguingly, we observed that CS induces TFEB accumulation in the insoluble protein fractions of Beas2b cells, which shows a partial rescue with GEM treatment. Moreover, TFEB knockdown induces oxidative stress, autophagy-impairment, and senescence, which can all be mitigated by GEM-mediated TFEB induction. Finally, in vivo studies were used to verify that CS-induced autophagy-impairment (increased Ub, p62, and valosin-containing protein in the insoluble protein fractions of lung/cell lysates), inflammation (interleukin-6 [IL-6] levels in bronchoalveolar lavage fluid and iNOS expression in lung sections), apoptosis (caspase-3/7), and resulting emphysema (hematoxylin and eosin [H&E]) can be controlled by GEM-mediated TFEB induction (p?<?0.05).InnovationCS exposure impairs autophagy in COPD-emphysema by inducing perinuclear localization of master autophagy regulator, TFEB, to aggresome-bodies.ConclusionTFEB-inducing drug(s) can control CS-induced TFEB/autophagy-impairment and COPD-emphysema pathogenesis. Antioxid. Redox Signal. 27, 150-167.

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MiR-4456/CCL3/CCR5 Pathway in the Pathogenesis of Tight Junction Impairment in Chronic Obstructive Pulmonary Disease.

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