TY - JOUR T1 - Function of monocytes and monocyte-derived macrophages in α<sub>1</sub>-antitrypsin deficiency JF - European Respiratory Journal JO - Eur Respir J SP - 365 LP - 376 DO - 10.1183/09031936.00046114 VL - 45 IS - 2 AU - Emily F.A. van’t Wout AU - Annemarie van Schadewijk AU - David A. Lomas AU - Jan Stolk AU - Stefan J. Marciniak AU - Pieter S. Hiemstra Y1 - 2015/02/01 UR - http://erj.ersjournals.com/content/45/2/365.abstract N2 - 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.No evidence for polymer formation and excess inflammatory responses in mononuclear phagocytes from AATD patients http://ow.ly/A0vTY ER -