Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency

Abstract

Background Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder most commonly secondary to a single mutation in the SERPINA1 gene (PI*Z) that causes misfolding and accumulation of alpha-1 antitrypsin (AAT) in hepatocytes and mononuclear phagocytes which reduces plasma AAT and creates a toxic gain of function. This toxic gain of function promotes a pro-inflammatory phenotype in macrophages that contributes to lung inflammation and early-onset COPD, especially in individuals who smoke cigarettes. The aim of this study is to determine the role of cigarette exposed AATD macrophages and bronchial epithelial cells in AATD-mediated lung inflammation. Methods Peripheral blood mononuclear cells from AATD and healthy individuals were differentiated into alveolar-like macrophages and exposed to air or cigarette smoke while in culture. Macrophage endoplasmic reticulum stress was quantified and secreted cytokines were measured using qPCR and cytokine ELISAs. To determine whether there is “cross talk” between epithelial cells and macrophages, macrophages were exposed to extracellular vesicles released by airway epithelial cells exposed to cigarette smoke and their inflammatory response was determined. Results AATD macrophages spontaneously produce several-fold more pro-inflammatory cytokines as compared to normal macrophages. AATD macrophages have an enhanced inflammatory response when exposed to cigarette smoke-induced extracellular vesicles (EVs) released from airway epithelial cells. Cigarette smoke-induced EVs induce expression of GM-CSF and IL-8 in AATD macrophages but have no effect on normal macrophages. Release of AAT polymers, potent neutrophil chemo attractants, were also increased from AATD macrophages after exposure to cigarette smoke-induced EVs. Conclusions The expression of mutated AAT confers an inflammatory phenotype in AATD macrophages which disposes them to an exaggerated inflammatory response to cigarette smoke-induced EVs, and thus could contribute to progressive lung inflammation and damage in AATD individuals.

Research progress of mitochondria in chronic obstructive pulmonary disease: a bibliometric analysis based on the Web of Science Core Collection

“…EVs, a general term for the nanoscale lipid bilayer vesicles released by virtually all cells upon activation, injury, or apoptosis, are key mediators of intercellular communication and alter the activity of peripheral or distant lung structural cells and associated immune cells to perform a variety of functions ( 48 ). Exposure of endothelial cells, epithelial cells, macrophages, neutrophils, and T lymphocytes to CS increase the release of EVs, which promote inflammation, injury, and apoptosis and are involved in the early development of COPD ( 49 - 52 ). It was found that cell-free mitochondrial DNA (mtDNA) levels were both elevated in the plasma of patients with COPD and in the serum of CS-induced emphysema mice.…”

Do Circulating Extracellular Vesicles Strictly Reflect Bronchoalveolar Lavage Extracellular Vesicles in COPD?

“…Preclinical studies have shown that cigarette smoke exposure can increase EV secretion from human airway epithelial cells [37,38] and modify their content [39]. These cigarette smoke-induced EVs can by themselves be harmful, promoting the shift of alveolar macrophages obtained from patients with familial emphysema towards a pro-inflammatory phenotype [40] and sharing procoagulant properties that may contribute to the increased cardiovascular and respiratory risk observed in smokers [41]. A robust increase in epithelial cell-derived EVs was observed as a consequence of hyperoxia-associated oxidative stress in mice BAL, suggesting that EVs shedding from airway cells might represent a common reaction to noxious stimuli [42,43].…”

Induction and Modulation of EVs by Cigarette Smoke and Their Relevance in Lung Disease: Recent Advances

“…The release of AAT polymer (potent neutrophil granulocyte chemoattractant) from AATD macrophages was also enhanced following exposure to CS-induced EVs. This may therefore lead to progressive lung inflammation and injury in individuals with AATD [35].…”