title: Function of monocytes and monocyte-derived macrophages in α1-antitrypsin deficiency.
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.
authors.affiliation: Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands Dept of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK.
authors.forename: Emily F A
authors.initials: EF
authors.lastname: Van't Wout
authors.affiliation: Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annemarie
authors.initials: A
authors.lastname: van Schadewijk
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, London, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Stolk
authors.affiliation: Dept of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Marciniak
authors.affiliation: Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands p.s.hiemstra@lumc.nl.
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
mesh_terms: D000328:Adult; D016207:Cytokines / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005541:Forced Expiratory Volume; D006720:Homozygote; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000235:genetics*; D015398:Signal Transduction; D056811:Unfolded Protein Response; D000515:alpha 1-Antitrypsin / Q000235:genetics; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood* / Q000150:complications
chemical_list: D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D016328:NF-kappa B; D000515:alpha 1-Antitrypsin