PMID- 34405715 OWN - NLM STAT- MEDLINE DCOM- 20211110 LR - 20221003 IS - 1522-1504 (Electronic) IS - 1040-0605 (Print) IS - 1040-0605 (Linking) VI - 321 IP - 4 DP - 2021 Oct 1 TI - TLR4 is required for macrophage efferocytosis during resolution of ventilator-induced lung injury. PG - L787-L801 LID - 10.1152/ajplung.00226.2021 [doi] AB - 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 h. On day 1 after mechanical ventilation, Tlr4(+/+) or Tlr4(-/-) 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(+/+) BMDMs. Importantly, these proresolving effects by Tlr4(+/+) BMDMs were abolished in mice receiving Tlr4(-/-) BMDMs. The number of macrophages containing apoptotic cells or bodies in bronchoalveolar lavage fluid was much less in mice receiving Tlr4(-/-) BMDMs than that in those receiving Tlr4(+/+) 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(+/+) BMDMs, but not Tlr4(-/-) BMDMs. Our results suggest that macrophage TLR4 promotes resolution of VILI via modulation of Mer-mediated efferocytosis. FAU - Su, Kai AU - Su K AD - Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois. AD - Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China. FAU - Bo, Lulong AU - Bo L AD - Faculty of Anesthesiology, Changhai Hospital, Shanghai, People's Republic of China. FAU - Jiang, Chunling AU - Jiang C AD - Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois. FAU - Deng, Xiaoming AU - Deng X AD - Faculty of Anesthesiology, Changhai Hospital, Shanghai, People's Republic of China. FAU - Zhao, You-Yang AU - Zhao YY AD - Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois. AD - Division of Critical Care, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois. FAU - Minshall, Richard D AU - Minshall RD AUID- ORCID: 0000-0003-3164-475X AD - Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois. AD - Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois. FAU - Hu, Guochang AU - Hu G AUID- ORCID: 0000-0002-7054-7867 AD - Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois. AD - Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois. LA - eng GR - R01 HL152696/HL/NHLBI NIH HHS/United States GR - R01HL152696/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ GR - R01 HL140409/HL/NHLBI NIH HHS/United States GR - R01 HL148810/HL/NHLBI NIH HHS/United States GR - R01HL104092/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ GR - R01 HL133951/HL/NHLBI NIH HHS/United States GR - R01 HL104092/HL/NHLBI NIH HHS/United States GR - R21AI152249/HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (DMID)/ GR - R21 AI152249/AI/NIAID NIH HHS/United States GR - R01 HL142636/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20210818 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (HSP70 Heat-Shock Proteins) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - EC 2.7.10.1 (Mertk protein, mouse) RN - EC 2.7.10.1 (c-Mer Tyrosine Kinase) RN - EC 3.4.24.86 (ADAM17 Protein) SB - IM MH - ADAM17 Protein/metabolism MH - Animals MH - Apoptosis/physiology MH - Bronchoalveolar Lavage Fluid/chemistry/cytology MH - Cell Count MH - Cells, Cultured MH - Female MH - HSP70 Heat-Shock Proteins/metabolism MH - Lung/pathology MH - Macrophages, Alveolar/*metabolism/transplantation MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neutrophils/*immunology MH - Phagocytosis/*physiology MH - Respiration, Artificial/adverse effects MH - Signal Transduction MH - Toll-Like Receptor 4/*metabolism MH - Ventilator-Induced Lung Injury/*pathology MH - c-Mer Tyrosine Kinase/metabolism PMC - PMC8560399 OTO - NOTNLM OT - TLR4 OT - efferocytosis OT - inflammation OT - macrophage OT - ventilator-induced lung injury COIS- No conflicts of interest, financial or otherwise, are declared by the authors. EDAT- 2021/08/19 06:00 MHDA- 2021/11/11 06:00 PMCR- 2022/10/01 CRDT- 2021/08/18 08:44 PHST- 2021/08/19 06:00 [pubmed] PHST- 2021/11/11 06:00 [medline] PHST- 2021/08/18 08:44 [entrez] PHST- 2022/10/01 00:00 [pmc-release] AID - L-00226-2021 [pii] AID - 10.1152/ajplung.00226.2021 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2021 Oct 1;321(4):L787-L801. doi: 10.1152/ajplung.00226.2021. Epub 2021 Aug 18.