1. Function of monocytes and monocyte-derived macrophages in α1-antitrypsin deficiency.
- Author
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Van't Wout EF, van Schadewijk A, Lomas DA, Stolk J, Marciniak SJ, and Hiemstra PS
- Subjects
- Adult, Cytokines metabolism, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress, Enzyme-Linked Immunosorbent Assay, Female, Forced Expiratory Volume, Homozygote, Humans, Inflammation metabolism, Lung metabolism, Macrophages cytology, Male, Middle Aged, Monocytes cytology, Mutation, NF-kappa B metabolism, Pulmonary Disease, Chronic Obstructive complications, Signal Transduction, Unfolded Protein Response, alpha 1-Antitrypsin genetics, alpha 1-Antitrypsin Deficiency complications, Macrophages metabolism, Monocytes metabolism, Pulmonary Disease, Chronic Obstructive genetics, alpha 1-Antitrypsin Deficiency blood
- Abstract
α1-antitrypsin deficiency is the most widely recognised genetic disorder causing chronic obstructive pulmonary disease (COPD). Mutant Z α1-antitrypsin expression has previously been linked to intracellular accumulation and polymerisation of this proteinase inhibitor. Subsequently, this has been described to underlie an exaggerated endoplasmic reticulum stress response and enhanced nuclear factor-κB signalling. However, whether monocyte-derived macrophages display the same features remains unknown. Monocytes from homozygous PiZZ α1-antitrypsin deficiency patients and PiMM controls were cultured for 6 days in the presence of granulocyte-macrophage or macrophage colony-stimulating factor to obtain pro- and anti-inflammatory macrophages (mφ-1 and mφ-2, respectively). We first showed that, in contrast to monocytes, pre-stressed mφ-1 and mφ-2 from healthy blood donors display an enhanced endoplasmic reticulum stress response upon a lipopolysaccharide trigger (XBP1 splicing, CHOP, GADD34 and GRP78 mRNA). However, this endoplasmic reticulum stress response did not differ between monocyte-derived macrophages and monocytes from ZZ patients compared to MM controls. Furthermore, these ZZ cells do not secrete higher cytokine levels, and α1-antitrypsin polymers were not detectable by ELISA. These data suggest that monocyte-derived macrophages are not the local source of Z α1-antitrypsin polymers found in the lung and that endoplasmic reticulum stress and pro-inflammatory cytokine release is not altered., (Copyright ©ERS 2015.)
- Published
- 2015
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