{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:18:27Z","timestamp":1792268307780,"version":"4.4.0"},"reference-count":45,"publisher":"American Physiological Society","issue":"4","funder":[{"DOI":"10.13039\/100015691","name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI152249"],"award-info":[{"award-number":["R21AI152249"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL152696"],"award-info":[{"award-number":["R01HL152696"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL104092"],"award-info":[{"award-number":["R01HL104092"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:p> Mechanical ventilation is a life-sustaining therapy for patients with respiratory failure but can cause further lung damage known as ventilator-induced lung injury (VILI). However, the intrinsic molecular mechanisms underlying recovery of VILI remain unknown. Phagocytosis of apoptotic cells (also known as efferocytosis) is a key mechanism orchestrating successful resolution of inflammation. Here we show the positive regulation of macrophage Toll-like receptor (TLR) 4 in efferocytosis and resolution of VILI. Mice were depleted of alveolar macrophages and then subjected to injurious ventilation (tidal volume, 20 mL\/kg) for 4\u2009h. On day 1 after mechanical ventilation, Tlr4<jats:sup>+\/+<\/jats:sup> or Tlr4<jats:sup>\u2212\/\u2212<\/jats:sup> bone marrow-derived macrophages (BMDMs) were intratracheally administered to alveolar macrophage-depleted mice. We observed that mice depleted of alveolar macrophages exhibited defective resolution of neutrophilic inflammation, exuded protein, lung edema, and lung tissue injury after ventilation, whereas these delayed responses were reversed by administration of Tlr4<jats:sup>+\/+<\/jats:sup> BMDMs. Importantly, these proresolving effects by Tlr4<jats:sup>+\/+<\/jats:sup> BMDMs were abolished in mice receiving Tlr4<jats:sup>\u2212\/\u2212<\/jats:sup> BMDMs. The number of macrophages containing apoptotic cells or bodies in bronchoalveolar lavage fluid was much less in mice receiving Tlr4<jats:sup>\u2212\/\u2212<\/jats:sup> BMDMs than that in those receiving Tlr4<jats:sup>+\/+<\/jats:sup> BMDMs. Macrophage TLR4 deletion facilitated a disintegrin and metalloprotease 17 maturation and enhanced Mer cleavage in response to mechanical ventilation. Heat shock protein 70 dramatically increased Mer tyrosine kinase surface expression, phagocytosis of apoptotic neutrophils, and rescued the inflammatory phenotype in alveolar macrophage-depleted mice receiving Tlr4<jats:sup>+\/+<\/jats:sup> BMDMs, but not Tlr4<jats:sup>\u2212\/\u2212<\/jats:sup> BMDMs. Our results suggest that macrophage TLR4 promotes resolution of VILI via modulation of Mer-mediated efferocytosis. <\/jats:p>","DOI":"10.1152\/ajplung.00226.2021","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T12:04:45Z","timestamp":1629288285000},"page":"L787-L801","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["TLR4 is required for macrophage efferocytosis during resolution of ventilator-induced lung injury"],"prefix":"10.1152","volume":"321","author":[{"given":"Kai","family":"Su","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois"},{"name":"Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulong","family":"Bo","sequence":"additional","affiliation":[{"name":"Faculty of Anesthesiology, Changhai Hospital, Shanghai, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunling","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Deng","sequence":"additional","affiliation":[{"name":"Faculty of Anesthesiology, Changhai Hospital, Shanghai, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, Illinois"},{"name":"Division of Critical Care, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3164-475X","authenticated-orcid":true,"given":"Richard D.","family":"Minshall","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois"},{"name":"Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7054-7867","authenticated-orcid":true,"given":"Guochang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois"},{"name":"Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201401-0168CP"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200860"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00055.2006"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e31823422c9"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-007-0959-6"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00334.2007"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00010.2011"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0232-1"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1378\/chest.12-2413"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/cc10437"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181bc7c17"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.29245\/2689-999X\/2017\/2.1107"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-11-126862"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.09.010"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200020"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302863"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601495"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180213"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313143"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.6.3860"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2008.31"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0240-6"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.263020"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200701-051OC"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00095"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.041"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181e89ab2"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02275"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4192"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nm1315"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.09.019"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021113-170408"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10105"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nri3600"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206641109"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1022-2"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2007-0306OC"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0611289"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-021634"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00501"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318182aef1"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1097\/00075198-200302000-00003"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2006.08.028"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300052"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2018.1439477"}],"container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajplung.00226.2021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T16:36:22Z","timestamp":1633970182000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajplung.00226.2021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,1]]},"references-count":45,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,10,1]]}},"alternative-id":["10.1152\/ajplung.00226.2021"],"URL":"https:\/\/doi.org\/10.1152\/ajplung.00226.2021","relation":{},"ISSN":["1040-0605","1522-1504"],"issn-type":[{"value":"1040-0605","type":"print"},{"value":"1522-1504","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,1]]},"assertion":[{"value":"2021-05-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}