{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:08:27Z","timestamp":1779149307944,"version":"3.51.4"},"reference-count":55,"publisher":"American Society for Clinical Investigation","issue":"12","funder":[{"name":"University of Florida","award":["UF project #00045513"],"award-info":[{"award-number":["UF project #00045513"]}]},{"name":"Alpha1 Foundation","award":["Alpha1 Foundation Research Professorship"],"award-info":[{"award-number":["Alpha1 Foundation Research Professorship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,6,22]]},"abstract":"<jats:p>\n                    \u03b1-1 antitrypsin (AAT) is a serine protease inhibitor that plays a pivotal role in maintaining lung homeostasis. The most common AAT allele associated with AAT deficiency (AATD) is PiZ. Z-AAT accumulates in cells due to misfolding, causing severe AATD. The major function of AAT is to neutralize neutrophil elastase in the lung. It is generally accepted that loss of antiprotease function is a major cause of COPD in individuals with AATD. However, it is now being recognized that the toxic gain-of-function effect of Z-AAT in macrophage likely contributes to lung disease. In the present study, we determined that TLR7 signaling is activated in Z-MDMs, and the expression level of NLRP3, one of the targets of TLR7 signaling, is significantly higher in Z- compared with M-MDMs. We also determined that the level of endosomal\n                    <jats:italic>Alu<\/jats:italic>\n                    RNA is significantly higher in Z-compared with M-MDMs.\n                    <jats:italic>Alu<\/jats:italic>\n                    RNA is a known endogenous ligand that activates TLR7 signaling. Z-AAT likely induces the expression of\n                    <jats:italic>Alu<\/jats:italic>\n                    elements in MDMs and accelerates monocyte death, leading to the higher level of endosomal\n                    <jats:italic>Alu<\/jats:italic>\n                    RNA in Z-MDMs. Taken together,this study identifies a mechanism responsible for the toxic gain of function of Z-AAT macrophages.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.158791","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T14:01:06Z","timestamp":1655820066000},"source":"Crossref","is-referenced-by-count":8,"title":["Alu RNA induces NLRP3 expression through TLR7 activation in \u03b1-1-antitrypsin\u2013deficient macrophages"],"prefix":"10.1172","volume":"7","author":[{"given":"Jungnam","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida, 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