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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-09-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-022-02161-z |
| _version_ | 1797636702107336704 |
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| author | Nazli Khodayari Regina Oshins Borna Mehrad Jorge E. Lascano Xiao Qiang Jesse R. West L. Shannon Holliday Jungnam Lee Gayle Wiesemann Soroush Eydgahi Mark Brantly |
| author_facet | Nazli Khodayari Regina Oshins Borna Mehrad Jorge E. Lascano Xiao Qiang Jesse R. West L. Shannon Holliday Jungnam Lee Gayle Wiesemann Soroush Eydgahi Mark Brantly |
| author_sort | Nazli Khodayari |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:38:56Z |
| format | Article |
| id | doaj.art-aeed486998b841e0a8aa558b3197c121 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-03-11T12:38:56Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-aeed486998b841e0a8aa558b3197c1212023-11-05T12:27:26ZengBMCRespiratory Research1465-993X2022-09-0123111410.1186/s12931-022-02161-zCigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiencyNazli Khodayari0Regina Oshins1Borna Mehrad2Jorge E. Lascano3Xiao Qiang4Jesse R. West5L. Shannon Holliday6Jungnam Lee7Gayle Wiesemann8Soroush Eydgahi9Mark Brantly10Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of FloridaDivision of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of FloridaDivision of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of FloridaDivision of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of FloridaMilliporeSigmaDivision of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of FloridaDepartment of Orthodontics, College of Dentistry, University of FloridaDivision of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of FloridaCollege of Medicine, University of FloridaDivision of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of FloridaDivision of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of FloridaAbstract 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.https://doi.org/10.1186/s12931-022-02161-zAlpha-1 antitrypsinMacrophagesExtracellular vesiclesCigarette smokeLung disease |
| spellingShingle | Nazli Khodayari Regina Oshins Borna Mehrad Jorge E. Lascano Xiao Qiang Jesse R. West L. Shannon Holliday Jungnam Lee Gayle Wiesemann Soroush Eydgahi Mark Brantly Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency Respiratory Research Alpha-1 antitrypsin Macrophages Extracellular vesicles Cigarette smoke Lung disease |
| title | Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency |
| title_full | Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency |
| title_fullStr | Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency |
| title_full_unstemmed | Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency |
| title_short | Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency |
| title_sort | cigarette smoke exposed airway epithelial cell derived evs promote pro inflammatory macrophage activation in alpha 1 antitrypsin deficiency |
| topic | Alpha-1 antitrypsin Macrophages Extracellular vesicles Cigarette smoke Lung disease |
| url | https://doi.org/10.1186/s12931-022-02161-z |
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