Erythromycin suppresses neutrophil extracellular traps in smoking-related chronic pulmonary inflammation

Abstract

Neutrophil extracellular traps (NETs) may play a critical role in smoking-related chronic airway inflammation. However, the mechanism by which NETs induced by cigarette smoke initiate the adaptive immunity in chronic obstructive pulmonary disease (COPD) is not fully understood. In this study, we explored the effects of NETs induced by cigarette smoke on the myeloid dendritic cells (mDCs) and Th1 and Th17 cells. Additionally, we observed the inhibitory effect of erythromycin on NETs induced by cigarette smoke. We found that elevated NET levels in the sputum of COPD patients were correlated with the circulating Th1 response, mDC activation and airflow limitation. NETs induced by cigarette smoke extract (CSE) could activate monocyte-derived mDCs and promote Th1 and Th17 differentiation in vitro. Erythromycin effectively inhibited NET formation induced by CSE. In vivo, erythromycin decreased NETs in the airway and ameliorated emphysema with Th1 and Th17 cell down-regulation and CD40+ and CD86+ mDCs suppression in mice chronically exposed to cigarette smoke. These findings provide direct evidence that NETs promote the differentiation of Th1 and Th17 and play a role in the adaptive immunity of smoking-related chronic lung inflammation. Erythromycin is a potential therapeutic strategy for NETs inhibition in COPD.

Neutrophils Modulate Fibrogenesis in Chronic Pulmonary Diseases

“…In COPD patients, NET levels are also elevated in the sputum, and they are similarly negatively correlated with lung function. In mice, reduced NET levels following erythromycin administration can alleviate emphysema and decrease the numbers of Th1, Th17, and myeloid dendritic cells ( 54 ). Furthermore, NET components stimulate histamine and leukotriene release, which may lead to further inflammatory changes in asthma and COPD.…”

“…In IPF, insufficient autophagy promotes fibrogenesis by stimulating fibroblast proliferation ( 76 ) and accelerates cellular senescence and myofibroblast differentiation of lung fibroblasts, suggesting the pro-fibrotic functions of insufficient autophagy in IPF ( 77 , 78 ). Macroautophagy and mitophagy are decreased in lung epithelial cells and lung fibroblasts of IPF patients ( 54 ). Mitophagy, a crucial process in cellular energy homeostasis, modulates macrophage apoptosis and stabilizes macrophages to release TGF-β1, thereby stimulating local fibroblast activation.…”

Cancer metastasis as a non-healing wound

“…Neutrophils have been shown to produce web-like DNA structures called neutrophil extracellular traps (NETs). 44 , 45 These entrap foreign bodies in the wound, such as extracellular bacteria, and further stimulate and recruit immune cells that promote the clearance of dying cells. 46 In the context of cancer, infiltration of neutrophils in the tumour microenvironment (TME) has been linked to the acquisition of metastatic traits.…”

The Role of Chronic Inflammation in Various Diseases and Anti‐inflammatory Therapies Containing Natural Products

“…[141] The underlying mechanisms may involve modulation of SIRT1 expression and NF-kB-dependent pro-inflammatory cytokine release, [142] inhibition of IL-17 and IL-23 mediated airway inflammation, [143] regulation of Th1, Th2, and Treg cell proportions, [144] and suppression of neutrophil extracellular trap (NET) formation. [145] Rapamycin (Figure 11), also known as sirolimus, is produced by the bacterium Streptomyces hygroscopicus, and is commonly used as an immunosuppressant in patients after organ transplant. Recent studies reveal that mammalian target of rapamycin (mTOR) signaling plays a critical role in sensing immune microenvironment and regulating the function of diverse immune cells, including cytotoxic T (Tc) cells, Th cells, Treg cells, dendritic cells, and monocytes.…”