Function of monocytes and monocyte-derived macrophages in α1-antitrypsin deficiency.

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Van't Wout, Emily FA 
van Schadewijk, Annemarie 
Lomas, David A 
Stolk, Jan 
Marciniak, Stefan J 

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.

Adult, Cytokines, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Enzyme-Linked Immunosorbent Assay, Female, Forced Expiratory Volume, Homozygote, Humans, Inflammation, Lung, Macrophages, Male, Middle Aged, Monocytes, Mutation, NF-kappa B, Pulmonary Disease, Chronic Obstructive, Signal Transduction, Unfolded Protein Response, alpha 1-Antitrypsin, alpha 1-Antitrypsin Deficiency
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European Respiratory Journal
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European Respiratory Society
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Medical Research Council (G1002610)
Medical Research Council (G0601840)
Medical Research Council (G0901786)
Wellcome Trust (100140/Z/12/Z)
This study was supported by a grant from the Netherlands Asthma Foundation (grant no. E.F.A. van't Wout is an European Alpha-1-Antitrypsin Laurell’s Training Awardee (sponsored by Grifols, Barcelona, Spain). D.A. Lomas is supported by the Medical Research Council (London, UK) and the NIHR UCLH Biomedical Research Centre (London). S.J. Marciniak is a Medical Research Council Senior Clinical Research Fellow (grant no. G1002610).