Alpha 1 Antitrypsin-Deficient Macrophages Have Impaired Efferocytosis of Apoptotic Neutrophils

Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder characterized by a low level of circulating AAT, which significantly reduces protection for the lower airways against proteolytic burden caused by neutrophils. Neutrophils, which are terminally differentiated innate immune ce...

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Published inFrontiers in immunology Vol. 11; p. 574410
Main Authors Lee, Jungnam, Lu, Yuanqing, Oshins, Regina, West, Jesse, Moneypenny, Craig G, Han, Kyudong, Brantly, Mark L
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 20.11.2020
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Abstract Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder characterized by a low level of circulating AAT, which significantly reduces protection for the lower airways against proteolytic burden caused by neutrophils. Neutrophils, which are terminally differentiated innate immune cells and play a critical role to clear pathogens, accumulate excessively in the lung of AATD individuals. The neutrophil burden in AATD individuals increases the risk for early-onset destructive lung diseases by producing neutrophil products such as reactive oxygen radicals and various proteases. The level of AAT in AATD individuals is not sufficient to inhibit the activity of neutrophil chemotactic factors such as CXCL-8 and LTB4, which could lead to alveolar neutrophil accumulation in AATD individuals. However, as neutrophils have a short lifespan, and apoptotic neutrophils are rapidly cleared by alveolar macrophages that outnumber the apoptotic neutrophils in the pulmonary alveolus, the increased chemotaxis activity does not fully explain the persistent neutrophil accumulation and the resulting chronic inflammation in AATD individuals. Here, we propose that the ability of alveolar macrophages to clear apoptotic neutrophils is impaired in AATD individuals and it could be the main driver to cause neutrophil accumulation in their lung. This study demonstrates that Z-AAT variant significantly increases the expression of pro-inflammatory cytokines including CXCL-8, CXCL1, LTB4, and TNFα in LPS-treated macrophages. These cytokines play a central role in neutrophil recruitment to the lung and in clearance of apoptotic neutrophils by macrophages. Our result shows that LPS treatment significantly reduces the efferocytosis ability of macrophages with the Z-AAT allele by inducing TNFα expression. We incubated monocyte-derived macrophages (MDMs) with apoptotic neutrophils and found that after 3 h of co-incubation, the expression level of CXCL-8 is reduced in M-MDMs but increased in Z-MDMs. This result shows that the expression of inflammatory cytokines could be increased by impaired efferocytosis. It indicates that the efferocytosis ability of macrophages plays an important role in regulating cytokine expression and resolving inflammation. Findings from this study would help us better understand the multifaceted effect of AAT on regulating neutrophil balance in the lung and the underlying mechanisms.
AbstractList Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder characterized by a low level of circulating AAT, which significantly reduces protection for the lower airways against proteolytic burden caused by neutrophils. Neutrophils, which are terminally differentiated innate immune cells and play a critical role to clear pathogens, accumulate excessively in the lung of AATD individuals. The neutrophil burden in AATD individuals increases the risk for early-onset destructive lung diseases by producing neutrophil products such as reactive oxygen radicals and various proteases. The level of AAT in AATD individuals is not sufficient to inhibit the activity of neutrophil chemotactic factors such as CXCL-8 and LTB4, which could lead to alveolar neutrophil accumulation in AATD individuals. However, as neutrophils have a short lifespan, and apoptotic neutrophils are rapidly cleared by alveolar macrophages that outnumber the apoptotic neutrophils in the pulmonary alveolus, the increased chemotaxis activity does not fully explain the persistent neutrophil accumulation and the resulting chronic inflammation in AATD individuals. Here, we propose that the ability of alveolar macrophages to clear apoptotic neutrophils is impaired in AATD individuals and it could be the main driver to cause neutrophil accumulation in their lung. This study demonstrates that Z-AAT variant significantly increases the expression of pro-inflammatory cytokines including CXCL-8, CXCL1, LTB4, and TNFα in LPS-treated macrophages. These cytokines play a central role in neutrophil recruitment to the lung and in clearance of apoptotic neutrophils by macrophages. Our result shows that LPS treatment significantly reduces the efferocytosis ability of macrophages with the Z-AAT allele by inducing TNFα expression. We incubated monocyte-derived macrophages (MDMs) with apoptotic neutrophils and found that after 3 h of co-incubation, the expression level of CXCL-8 is reduced in M-MDMs but increased in Z-MDMs. This result shows that the expression of inflammatory cytokines could be increased by impaired efferocytosis. It indicates that the efferocytosis ability of macrophages plays an important role in regulating cytokine expression and resolving inflammation. Findings from this study would help us better understand the multifaceted effect of AAT on regulating neutrophil balance in the lung and the underlying mechanisms.
Author Brantly, Mark L
Han, Kyudong
Lee, Jungnam
Moneypenny, Craig G
Oshins, Regina
Lu, Yuanqing
West, Jesse
AuthorAffiliation 1 Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida , Gainesville, FL , United States
2 Department of Microbiology, College of Science and Technology, Dankook University , Cheonan , South Korea
3 DKU-Theragen Institute for NGS Analysis , Cheonan , South Korea
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Keywords cytokine
macrophage
Alpha 1 antitrysin
neutrophil
AAT deficiency
efferocytosis
Language English
License Copyright © 2020 Lee, Lu, Oshins, West, Moneypenny, Han and Brantly.
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This article was submitted to Cytokines and Soluble Mediators in Immunity, a section of the journal Frontiers in Immunology
Edited by: Ola Grimsholm, University of Gothenburg, Sweden
Reviewed by: Sabina Janciauskiene, Hannover Medical School, Germany; Kylie Belchamber, University of Birmingham, United Kingdom
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Snippet Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disorder characterized by a low level of circulating AAT, which significantly reduces...
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StartPage 574410
SubjectTerms AAT deficiency
Alpha 1 antitrysin
alpha 1-Antitrypsin - genetics
alpha 1-Antitrypsin - immunology
alpha 1-Antitrypsin Deficiency - genetics
alpha 1-Antitrypsin Deficiency - immunology
Apoptosis - immunology
Chemotaxis, Leukocyte
cytokine
Cytokines - metabolism
efferocytosis
Genotype
Humans
Immunology
Lipopolysaccharides - pharmacology
macrophage
Macrophages - drug effects
Macrophages - immunology
Macrophages - metabolism
neutrophil
Neutrophils - immunology
Neutrophils - metabolism
Phagocytosis - drug effects
Phagocytosis - genetics
Phagocytosis - immunology
Tumor Necrosis Factor-alpha - immunology
Tumor Necrosis Factor-alpha - metabolism
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Title Alpha 1 Antitrypsin-Deficient Macrophages Have Impaired Efferocytosis of Apoptotic Neutrophils
URI https://www.ncbi.nlm.nih.gov/pubmed/33329539
https://search.proquest.com/docview/2470899086
https://pubmed.ncbi.nlm.nih.gov/PMC7714766
https://doaj.org/article/95e5260050ed4bed8510fc0b10c58a73
Volume 11
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