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1 Antitrypsin Deficiency Α with Activation in Monocytes From Evidence for Unfolded Protein Response Activation in Monocytes from Individuals with α-1 Antitrypsin Deficiency This information is current as Tomás P. Carroll, Catherine M. Greene, Catherine A. of September 24, 2021. O'Connor, Áine M. Nolan, Shane J. O'Neill and Noel G. McElvaney J Immunol 2010; 184:4538-4546; Prepublished online 12 March 2010; doi: 10.4049/jimmunol.0802864 Downloaded from http://www.jimmunol.org/content/184/8/4538 References This article cites 63 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/184/8/4538.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Evidence for Unfolded Protein Response Activation in Monocytes from Individuals with a-1 Antitrypsin Deficiency Toma´s P. Carroll, Catherine M. Greene, Catherine A. O’Connor, A´ ine M. Nolan, Shane J. O’Neill, and Noel G. McElvaney The hereditary disorder a-1 antitrypsin (AAT) deficiency results from mutations in the SERPINA1 gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT deficiency occurs because of the Z mutation, causing the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). This leads to ER stress and contributes significantly to the liver disease associated with the condition. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. In this study we show for the first time that the unfolded protein response (UPR) is activated in quiescent monocytes from ZZ individuals. Activating transcription factor 4, X-box binding protein 1, and a subset of genes involved in the UPR are increased in monocytes from ZZ compared with MM individuals. This contributes to an in- Downloaded from flammatory phenotype with ZZ monocytes exhibiting enhanced cytokine production and activation of the NF-kB pathway when compared with MM monocytes. In addition, we demonstrate intracellular accumulation of AAT within the ER of ZZ monocytes. These are the first data showing that Z AAT protein accumulation induces UPR activation in peripheral blood monocytes. These findings change the current paradigm regarding lung inflammation in AAT deficiency, which up until now was derived from the protease–anti-protease hypothesis, but which now must include the exaggerated inflammatory response generated by accumulated aberrantly folded AAT in circulating blood cells. The Journal of Immunology, 2010, 184: 4538–4546. http://www.jimmunol.org/ ewly synthesized proteins destined for secretion (such as protein synthesis, transcriptional induction of ER-resident chaper- a-1 antitrypsin [AAT]) are transported into the lumen of ones, and ER-associated degradation (ERAD) (2). Three integral ER- N the endoplasmic reticulum (ER) where they are folded and resident transmembrane sensors, protein kinase RNA-like ER kinase assembled. ER homeostasis is essential for normal cell function and (PERK), activating transcription factor 6 (ATF6), and inositol re- survival. Environmental perturbations, such as disturbances in cal- quiring kinase 1 (IRE1), form a tripartite management system that cium storage, compromise the ER protein folding capacity resulting coordinates the unfolded protein response (UPR) (3). in the accumulation of unfolded or misfolded protein within the ER. The first and immediate step in UPR engagement is translational by guest on September 24, 2021 Any imbalance between the load of unfolded proteins entering the ER attenuation. This reduces the load of host protein synthesis in the ER and the ability of the ER to process this load is termed ER stress. ER and prevents further accumulation of unfolded proteins. This is stress can also be induced by a range of pathophysiological con- carried out by PERK, through phosphorylation of eukaryotic initi- ditions, including ischemia, diabetes, viral infection, and mutations ation factor 2 (eIF2) on its a subunit (eIF2a) (4). Although it reduces that impair host protein folding (1). To maintain homeostasis, the ER global protein synthesis, eIF2a phosphorylation paradoxically has evolved to sense stress and transduce signals to the cytoplasm and promotes the translation of ATF4 mRNA, a basic leucine zipper the nucleus, striving to adapt for survival or induce apoptosis. The transcription factor. ATF4 is involved in the expression of genes protective system includes the translational attenuation of global essential for amino acid import, glutathione biosynthesis, and re- sistance to oxidative stress (5). The transcriptional arm of the UPR Respiratory Research Division, Royal College of Surgeons in Ireland, Education and uses IRE1 and ATF6, which regulate chaperone induction, ERAD, Research Centre, Beaumont Hospital, Dublin, Ireland and expansion of the ER in response to ER stress (2). IRE1 is an Received for publication August 29, 2008. Accepted for publication February 15, endoribonuclease, and ER stress causes it to oligomerize and acti- 2010. vate its RNase domain (6), and a target of IRE1 is the basic leucine This work was supported by financial assistance from the Alpha One Foundation zipper transcription factor X-box binding protein 1 (XBP-1). The (Ireland), the Alpha One Foundation (U.S.), the Health Research Board, the Medical Research Charities Group, the Children’s Research Centre Crumlin Hospital, the stress-induced spliced form of XBP-1 travels into the nucleus and Programme for Research in Third Level Institutes, Talecris Biotherapeutics, and can bind to both ER stress response elements and UPR elements, the Royal College of Surgeons in Ireland. Confocal imaging experiments were per- formed on equipment supported by the Higher Education Authority of Ireland activating the transcription of ER chaperone genes, ER quality through the National Biophotonics and Imaging Platform Ireland. T.P.C. is a recipient control genes, and folding enzymes (7, 8). In a later phase of the of the European Alpha-1-Antitrypsin Laurell’s Training Award (eALTA) 2007. UPR components of the ERAD pathway including p97/valosin- Address correspondence and reprint requests to Dr. Toma´s Carroll, Respiratory Re- containing protein (p97/VCP) and Derlin-1 are called into action. search Division, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. E-mail address: [email protected] ERAD is the process whereby terminally misfolded ER proteins are Abbreviations used in this paper: AAT, a-1 antitrypsin; AATD, a-1 antitrypsin de- prevented from progressing along the secretory pathway, retro- ficiency; ATF, activating transcription factor; CF, cystic fibrosis; CFTR, CF trans- translocated from the ER lumen into the cytoplasm, and degraded by membrane regulator; eIF2, eukaryotic initiation factor 2; ER, endoplasmic reticulum; ERAD, ER-associated degradation; grp, glucose-regulated protein; Hsp, heat shock the ubiquitin-proteasome system (9). protein; IRE1, inositol requiring kinase 1; p97/VCP, p97/valosin-containing protein; AAT deficiency (AATD) is a genetic disorder characterized by PERK, protein kinase RNA-like ER kinase; TG, thapsigargin; TM, tunicamycin; decreased serum levels of a serine protease inhibitor and classically UPR, unfolded protein response; XBP-1, X-box binding protein 1. presents with emphysema in young to middle-aged adults and liver Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 disease in childhood and occasionally in adulthood (10, 11). www.jimmunol.org/cgi/doi/10.4049/jimmunol.0802864 The Journal of Immunology 4539 However, AATD can be classified as an ER stress-related disease Materials and Methods as it involves mutations that affect AAT structure, resulting in re- Subjects tention of abnormal AAT cargo in the ER (12). AAT is a 52 kDa gp The study group consisted of healthy MM volunteers (n = 7, 5 males, 2 produced primarily by hepatocytes and its main site of action is the females) and asymptomatic ZZ AAT (n = 7, 4 males, 3 females, mean lung, where it serves to protect the fragile alveolar, connective, and forced expiratory volume in one second 79.9 6 8.6% predicted) in- dividuals. All ZZ patients included in the study were in a stable, non- epithelial tissues from proteolytic attack (13). AAT is the archetype exacerbated phase. The exclusion criteria were smoking, liver diseases, of the serine protease inhibitor or serpin superfamily, inhibiting the vasculitic, or other extrapulmonary diseases. The healthy volunteers showed serine proteases neutrophil elastase, cathepsin G, and proteinase no evidence of any disease and had no respiratory symptoms; none were on medication and all were MM phenotype with serum AAT concentrations
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