{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T17:50:36Z","timestamp":1794505836827,"version":"4.9.1"},"reference-count":40,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T00:00:00Z","timestamp":1709078400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Medical Research Charities Group\/Health Research Board Ireland","award":["MRCG-2018-04"],"award-info":[{"award-number":["MRCG-2018-04"]}]},{"DOI":"10.13039\/100001448","name":"US Alpha-1 Foundation","doi-asserted-by":"crossref","award":["614218"],"award-info":[{"award-number":["614218"]}],"id":[{"id":"10.13039\/100001448","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001448","name":"US Alpha-1 Foundation","doi-asserted-by":"crossref","award":["615848"],"award-info":[{"award-number":["615848"]}],"id":[{"id":"10.13039\/100001448","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Thorax"],"accepted":{"date-parts":[[2024,2,2]]},"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1\u03b2 secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d\/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1\u03b2 secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>C3d acting via CR3 induces NLRP3 and pro-IL-1\u03b2 production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1\u03b2 secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0\u00b11.2 \u00b5g\/mL vs 1.3\u00b10.5 \u00b5g\/mL respectively, p&lt;0.0001) and IL-1\u03b2 (115.4\u00b130 pg\/mL vs 73.3\u00b120 pg\/mL, respectively, p&lt;0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.<\/jats:p><\/jats:sec>","DOI":"10.1136\/thorax-2023-221071","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T18:20:35Z","timestamp":1709144435000},"page":"822-833","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Monocyte NLRP3 inflammasome and interleukin-1\u03b2 activation modulated by alpha-1 antitrypsin therapy in deficient individuals"],"prefix":"10.1136","volume":"79","author":[{"given":"Debananda","family":"Gogoi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Casey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory","family":"Baird","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azeez","family":"Yusuf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Forde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"O' Brien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse R","family":"West","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Flagg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel G","family":"McElvaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Eden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0189-1565","authenticated-orcid":false,"given":"Mark L","family":"Brantly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Geraghty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1922-0447","authenticated-orcid":false,"given":"Emer P","family":"Reeves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"2025031304001669000_79.9.822.1","doi-asserted-by":"publisher","DOI":"10.1007\/s00005-012-0162-5"},{"key":"2025031304001669000_79.9.822.2","doi-asserted-by":"crossref","unstructured":"Greene CM , Marciniak SJ , Teckman J , et al . Alpha1-Antitrypsin deficiency. Nat Rev Dis Primers 2016;2. doi:10.1038\/nrdp.2016.51","DOI":"10.1038\/nrdp.2016.51"},{"key":"2025031304001669000_79.9.822.3","doi-asserted-by":"publisher","DOI":"10.1038\/357605a0"},{"key":"2025031304001669000_79.9.822.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra010772"},{"key":"2025031304001669000_79.9.822.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp0900449"},{"key":"2025031304001669000_79.9.822.6","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201108-1428CI"},{"key":"2025031304001669000_79.9.822.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60860-1"},{"key":"2025031304001669000_79.9.822.8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S2213-2600(16)30430-1","article-title":"Long-term efficacy and safety of Alpha1 Proteinase inhibitor treatment for emphysema caused by severe Alpha1 Antitrypsin deficiency: an open-label extension trial (RAPID-OLE)","volume":"5","author":"McElvaney","year":"2017","journal-title":"Lancet Respir Med"},{"key":"2025031304001669000_79.9.822.9","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1164\/rccm.201807-1380LE","article-title":"Lectin complement pathway in emphysema","volume":"199","author":"Serban","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2025031304001669000_79.9.822.10","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2019-214076"},{"key":"2025031304001669000_79.9.822.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2008.03.018"},{"key":"2025031304001669000_79.9.822.12","doi-asserted-by":"crossref","DOI":"10.1186\/s12931-023-02343-3","article-title":"Lung inflammation in Alpha-1-Antitrypsin deficient individuals with normal lung function","volume":"24","author":"Kokturk","year":"2023","journal-title":"Respir Res"},{"key":"2025031304001669000_79.9.822.13","first-page":"13209","article-title":"Nlrp3 Inflammasome is essential for the development of chronic obstructive pulmonary disease","volume":"8","author":"Yang","year":"2015","journal-title":"Int J Clin Exp Pathol"},{"key":"2025031304001669000_79.9.822.14","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.158791","article-title":"Alu RNA induces Nlrp3 expression through Tlr7 activation in \u0391-1-Antitrypsin\u2013deficient Macrophages","volume":"7","author":"Lee","year":"2022","journal-title":"JCI Insight"},{"key":"2025031304001669000_79.9.822.15","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.02716","article-title":"Structural Immunology of complement receptors 3 and 4","volume":"9","author":"Vorup-Jensen","year":"2018","journal-title":"Front Immunol"},{"key":"2025031304001669000_79.9.822.16","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202106-1426OC"},{"key":"2025031304001669000_79.9.822.17","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1164\/rccm.201905-1013OC","article-title":"Specific inhibition of the Nlrp3 Inflammasome as an antiinflammatory strategy in cystic fibrosis","volume":"200","author":"McElvaney","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2025031304001669000_79.9.822.18","doi-asserted-by":"crossref","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-kappaB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct Target Ther"},{"key":"2025031304001669000_79.9.822.19","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/sj.leu.2403653","article-title":"Pi3-kinase\/AKT is Constitutively active in primary acute myeloid leukaemia cells and regulates survival and Chemoresistance via NF-kB, Mapkinase and P53 pathways","volume":"19","author":"Grandage","year":"2005","journal-title":"Leukemia"},{"key":"2025031304001669000_79.9.822.20","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41423-021-00670-3","article-title":"An update on the regulatory mechanisms of Nlrp3 Inflammasome activation","volume":"18","author":"Paik","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"2025031304001669000_79.9.822.21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.7.2466"},{"key":"2025031304001669000_79.9.822.22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802864"},{"key":"2025031304001669000_79.9.822.23","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00046114"},{"key":"2025031304001669000_79.9.822.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713689115"},{"key":"2025031304001669000_79.9.822.25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.7.2466"},{"key":"2025031304001669000_79.9.822.26","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1056\/NEJMc1915484","article-title":"Consequences of abrupt cessation of Alpha1-Antitrypsin replacement therapy","volume":"382","author":"McElvaney","year":"2020","journal-title":"N Engl J Med"},{"key":"2025031304001669000_79.9.822.27","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1164\/rccm.201901-0010OC","article-title":"The biological effects of double-dose Alpha-1 Antitrypsin augmentation therapy","volume":"200","author":"Campos","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2025031304001669000_79.9.822.28","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.124388"},{"key":"2025031304001669000_79.9.822.29","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt487"},{"key":"2025031304001669000_79.9.822.30","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.intimp.2017.12.016","article-title":"Inflammation induced ER stress affects absorptive intestinal epithelial cells function and integrity","volume":"55","author":"Chotikatum","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"2025031304001669000_79.9.822.31","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1165\/rcmb.2021-0433OC","article-title":"Alpha-1 Antitrypsin therapy modifies neutrophil adhesion in patients with obstructive lung disease","volume":"67","author":"McEnery","year":"2022","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2025031304001669000_79.9.822.32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901363"},{"key":"2025031304001669000_79.9.822.33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.11.7611"},{"key":"2025031304001669000_79.9.822.34","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2017-210326"},{"key":"2025031304001669000_79.9.822.35","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2020.106394","article-title":"Ameliorative effect of selective Nlrp3 Inflammasome inhibitor Mcc950 in an Ovalbumin-induced allergic rhinitis murine model","volume":"83","author":"Zhang","year":"2020","journal-title":"Int Immunopharmacol"},{"key":"2025031304001669000_79.9.822.36","doi-asserted-by":"crossref","DOI":"10.1183\/13993003.00119-2019","article-title":"The Nlrp3 Inflammasome pathway is activated in Sarcoidosis and involved in Granuloma formation","volume":"55","author":"Huppertz","year":"2020","journal-title":"Eur Respir J"},{"key":"2025031304001669000_79.9.822.37","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198704233161704"},{"key":"2025031304001669000_79.9.822.38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400132"},{"key":"2025031304001669000_79.9.822.39","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1080\/17476348.2023.2174973","article-title":"Alpha-1 Antitrypsin deficiency: Current therapy and emerging targets","volume":"17","author":"McElvaney","year":"2023","journal-title":"Expert Rev Respir Med"},{"key":"2025031304001669000_79.9.822.40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402956"}],"container-title":["Thorax"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/thorax-2023-221071","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T11:02:27Z","timestamp":1741863747000},"score":1,"resource":{"primary":{"URL":"https:\/\/thorax.bmj.com\/lookup\/doi\/10.1136\/thorax-2023-221071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,28]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,8,19]]},"published-print":{"date-parts":[[2024,9]]}},"alternative-id":["10.1136\/thorax-2023-221071"],"URL":"https:\/\/doi.org\/10.1136\/thorax-2023-221071","relation":{},"ISSN":["0040-6376","1468-3296"],"issn-type":[{"value":"0040-6376","type":"print"},{"value":"1468-3296","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,28]]}}}