Release and Actions of Inflammatory Exosomes in Pulmonary Emphysema: Potential Therapeutic Target of Acupuncture

Abstract

Background: Exosomes have been reported to mediate activation of the inflammatory response by secretion of inflammasome products such as IL-1β or IL-18 and that changes in exosomes production or secretion may be a therapeutic target for treatment of a variety of different chronic diseases. The present study tested the hypothesis that exosome-mediated release of NLRP3 inflammasome products instigates the inflammatory response in the lung during emphysema, a type of chronic obstructive pulmonary disease (COPD) and that electroacupuncture (EA) may attenuate emphysema by inhibition of NLRP3 inflammasome activation and consequent inflammation. Methods: The COPD mice model was developed by injecting porcine pancreatic elastase (PPE) via puncture tracheotomy and instillation. EA (4 Hz/20 Hz, 1 to 3 mA) was applied to the bilateral BL13 and ST36 for 30 min, once every other day for 2 weeks. Micro computed tomography (micro-CT) was performed to measure lung function. Histopathological changes in the lungs were displayed by HE staining. Results: In a mouse model of porcine pancreatic elastase (PPE)-induced emphysema, the lung tissue was found to display several key features of emphysema, including alveolar septal thickening, enlarged alveoli, interstitial edema, and inflammatory cells infiltration. Lungs of mice receiving PPE exhibited substantially increased low attenuation area (LAA) in micro-CT images. The colocalization of NLRP3 vs ASC or caspase-1 detected by confocal microscopy was shown to increase in both bronchial and alveolar walls, indicating the increased formation of NLRP3 inflammasomes. IL-1β, a prototype NLRP3 inflammasome activating product, was also found to have increased in the lung during emphysema, which was colocalized with CD63 (an exosome marker), an indicative of inflammatory exosome formation. By nanoparticle tracking analysis (NTA), IL-1β-containing exosomes were shown to significantly increase in the bronchoalveolar lavage (BAL) from mice with emphysema. Therapeutically, IL-1β production in the lung during emphysema was significantly reduced by EA at the acupoint Feishu (BL13) and Zusanli (ST36), accompanied by decreased colocalization of NLRP3 vs ASC or caspase-1. Increased exosome release into BAL during emphysema was shown to be significantly attenuated in EA-treated mice compared to their controls. However, EA of non-specific BL23 together with ST36 acupoint had no effects on NLRP3 inflammasome activation, exosome release and associated lung pathology during emphysema. Conclusion: NLRP3 inflammasome activation in concert with increased release of exosomes containing IL-1β or other inflammasome products contributes to the development of lung inflammation and injury during PPE-induced emphysema and that EA of lung-specific acupoints attenuates inflammasome activation and exosome release, thereby reducing inflammatory response in the lung of mice with emphysema.

Extracellular vesicles and chronic obstructive pulmonary disease (COPD): a systematic review

“…Nieri et al [ 23 ] observed an increase in monocyte-derived EVs with COPD severity. Zou et al [ 30 ] noted significantly increased levels of IL-1B-containing exosomes in the bronchoalveolar lavage from mice with emphysema, but did not specify the cells the exosomes were derived from.…”

“…Eleven studies [ 23 , 25 – 34 ] observed EVs from other cell types involved in COPD (Table 3 ). Seven of the studies [ 25 , 26 , 28 , 30 – 33 ] investigated EVs from epithelial cells, two studies [ 27 , 34 ] observed EVs from neutrophils, one study [ 29 ] examined microparticles from T lymphocytes and one study [ 30 ] did not specify the cells types EVs were derived from. Six studies investigating EVs from epithelial cells carried out in vitro studies, and three of the studies carried out further analysis in vivo in mice only [ 26 ] or in vivo mice and ex vivo human [ 28 ].…”

“…Isolated CD4+ and CD8+ TLMPs reduced cell viability and induced significant production of inflammatory cytokines including IL-6, MCP-1, MCP-2, MMP-9 and TNF-α in HBEs, while the levels of anti-inflammatory cytokine IL-10 were decreased. TLMPs in the airways may lead to airway epithelial injury and inflammation and serve essential roles in the pathophysiology of COPD Zou et al, 2021 [ 30 ] Release and actions of inflammatory exosomes in pulmonary emphysema: potential therapeutic target of acupuncture Investigate if exosome-mediated release of NLRP3 inflammasome products instigates the inflammatory response in the lung during emphysema In vivo Mice NLRP3 inflammasome activation and associated inflammatory exosome release are critically implicated in the development of inflammation during PPE-induced emphysema Wang et al, 2021 [ 31 ] Cigarette smoke extract-treated airway epithelial cells-derived exosomes promote M1 macrophage polarization in chronic obstructive pulmonary disease Investigate whether the exosomes derived from CSE-treated AECs regulate macrophage polarization and subsequently affect the progression of COPD by modulating TREM-1 expression In vitro Exosomes derived from CSE-treated AECs aggravate CS-induced lung inflammation and tissue injury in mice, which is associated with the promotion of M1 macrophage polarization by these exosomes through upregulation of TREM-1 expression Song et al, 2021 [ 32 ] Exosomal lncRNA TCONS_00064356 derived from injured alveolar epithelial type II cells affects the biological characteristics of mesenchymal stem cells Investigate whether injured alveolar cells communicate with MSCs via secretion of exosomes and investigate the role of exosomal lncRNAs derived from injured alveolar cells to identify novel therapeutic targets for COPD In vitro Injured AEC-II cells can affect the biological characteristics of MSCs via secretion of exosomes and the dysregulated exosomal lncRNAs that may be involved in this process were screened out Xia et al, 2022 [ 33 ] The aberrant cross-talk of epithelium-macrophages via METTL3-regulated extracellular vesicle miR-93 in smoking-induced emphysema Assess the role of EV miR-93 in bronchial epithelium exposed to cigarette smoke and the cross-talk between these cells and macrophages in smoking-induced emphysema In vitro CS exposure induces elevation of METTL3-promoted miR-93 maturation, and miR-93 is transferred from bronchial epithelial cells into macrophages by EVs. In macrophages, miR-93 activates the JNK pathway by targeting DUSP2, which increases the levels of MMP9 and MMP12, inducing elastin degradation.…”

Acupuncture Synergized With Bortezomib Improves Survival of Multiple Myeloma Mice via Decreasing Metabolic Ornithine

“…The mice were divided into four groups as follows: model control (C, only modeling, n=10) group, bortezomib (V, n=10) treatment group, acupuncture (A, n=9) treatment group, and VA (n=8) treatment group. One day later, mice in three treatment groups were treated by different methods, containing intraperitoneal injection of 1.2 mg/ml V twice a week or/and electroacupuncture (Model SDZ-II, Suzhou Medical Appliance Factory, Suzhou, China) stimulation of Hegu ( 29 ) and Zusanli ( 30 , 31 ) points (2/100 Hz, 2 mA) three times a week until all the mice were dead.…”

Electroacupuncture Alleviates LPS-Induced ARDS Through α7 Nicotinic Acetylcholine Receptor-Mediated Inhibition of Ferroptosis

“…For instance, Liu et al (7) reported that EA stimulation reduces the release of inflammatory factors through neural regulation, thereby inhibiting the systemic inflammatory response induced by endotoxin; Yang et al (8) confirmed that EA treatment inhibits the production of proinflammatory factors, attenuates the inflammatory response of the intestine and promotes gastrointestinal peristalsis. Recent studies have also shown that EA stimulation attenuates excessive immune responses in the lung tissue and relieves lung damage by inhibiting the activation of the nod-like receptor pyrin domaincontaining 3 (NLRP3) inflammasome and the production of inflammatory exosomes (9,10). Although these studies have shown that EA treatment exerts an anti-inflammatory impact on ALI/ARDS induced by a variety of inflammatory diseases, the underlying mechanism has not yet been clarified.…”