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

Abstract

α 1 -antitrypsin deficiency is the most widely recognised genetic disorder causing chronic obstructive pulmonary disease (COPD). Mutant Z α 1 -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 α 1 -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 (mw-1 and mw-2, respectively).We first showed that, in contrast to monocytes, pre-stressed mw-1 and mw-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 α 1 -antitrypsin polymers were not detectable by ELISA.These data suggest that monocyte-derived macrophages are not the local source of Z α 1 -antitrypsin polymers found in the lung and that endoplasmic reticulum stress and pro-inflammatory cytokine release is not altered. @ERSpublicationsNo evidence for polymer formation and excess inflammatory responses in mononuclear phagocytes from AATD patients

Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance

“…Although polymers formed from the folded state are typically studied because of experimental ease of generation, they might nevertheless still be of physiological and pathological importance, since it has been observed that polymers of Z α 1 PI also occur in circulation [62] and are even found to co-localize with neutrophils in lung alveoli [63], though not within the neutrophils [64]. Understanding whether such polymers use the same mechanism of formation as polymers formed intracellularly during folding is therefore of high significance.…”

Molecular cloning, genomic structure, polymorphism analysis and recombinant expression of a α1-antitrypsin like gene from swamp eel, Monopterus albus

“…Alpha-1 antitrypsin (AAT), a major serine proteinase inhibitor (Serpin), is synthesized primarily in the liver, but is also produced in extra-hepatic tissues and cells, including neutrophils, monocytes, alveolar macrophages, and intestinal and corneal epithelium [1]. AAT functions primarily to protect lung tissue from the destructive effects of serine proteases, such as neutrophil elastase, proteinase 3 and cathepsin G, which are released by degranulating neutrophils [2]. Although AATs are associated with maintaining protease-antiprotease homeostasis, their principle efficiency is in regulating inflammatory responses rather than inhibiting specific proteases [3].…”

α1‐Antitrypsin Deficiency

“…We also consider existing treatment options and developments that 7 might further improve the outlook for 1-antitrypsin deficient individuals. 8 9 10 [H1] Epidemiology 11 1-antitrypsin deficiency is relatively common but widely and persistently under-12 recognized 2,3 . This section considers the world-wide prevalence of 1-antitrypsin 13 deficiency, evidence that it is under-recognized, and the reasons for under-recognition.…”

“…Estimates of the mean interval between first symptom (usually dyspnoea) and initial 11 diagnosis range from 5.6 -8.3 years 3,9 . Diagnostic delay intervals remain as long in 12 studies from 2013 as they were in the earliest study in 1995, suggesting little 13 improvement in detection pace over nearly two decades despite the publication of many 14 guidelines 10 which recommend that all COPD patients should be tested for 1-antitrypsin 15 deficiency.…”

“…Similarly, the number of healthcare providers that affected individuals see 16 before the diagnosis is first made has not lessened over time 2 . In addition to delaying any 17 management interventions for the affected individual (e.g., smoking cessation, 18 consideration of augmentation therapy) and identification of family members at risk, the 19 need to see multiple healthcare providers before initial diagnosis and the associated 20 diagnostic delay have been associated with adverse psychosocial effects 3 . In the context 21 that establishing a diagnosis of 1-antitrypsin deficiency can directly affect both the 22 patient's clinical management and can identify potential risk among the patient's family 23 members, continuing under-recognition of 1-antitrypsin deficiency provides a world-24 wide call to action for enhanced detection by healthcare providers.…”