title: Inactivation of Rab11a GTPase in Macrophages Facilitates Phagocytosis of Apoptotic Neutrophils.
abstract: The timely and efficient clearance of apoptotic neutrophils by macrophages (efferocytosis) is required for the resolution of inflammation and tissue repair, but the regulatory mechanisms remain unclear. In this study, we investigated the role of the small GTPase Ras-related protein in brain (Rab)11a in regulating efferocytosis, and on this basis the resolution of inflammatory lung injury. We observed that apoptotic neutrophil feeding induced a rapid loss of Rab11a activity in bone marrow-derived macrophages and found that depletion of Rab11a in macrophages by small interfering RNA dramatically increased the phagocytosis of apoptotic neutrophils compared with control cells. Additionally, overexpression of wild-type Rab11a inhibited macrophage efferocytosis, whereas overexpression of dominant-negative Rab11a (Rab11a S25N) increased the clearance of apoptotic neutrophils. Rab11a knockdown also increased the surface level of CD36 in macrophages, but it reduced cell surface expression of a disintegrin and metalloproteinase (ADAM) 17. Depletion of ADAM17 rescued the decreased surface CD36 expression found in macrophages overexpressing wild-type Rab11a. Also, blockade of CD36 abolished the augmented efferocytosis seen in Rab11a-depleted macrophages. In mice challenged with endotoxin, intratracheal instillation of Rab11a-depleted macrophages reduced neutrophil count in bronchoalveolar lavage fluid, increased the number of macrophages containing apoptotic neutrophils, and prevented inflammatory lung injury. Thus, Rab11a inactivation in macrophages as a result of apoptotic cell binding initiates phagocytosis of apoptotic neutrophils via the modulation of ADAM17-mediated CD36 cell surface expression. Our results raise the possibility that inhibition of Rab11a activity in macrophages is a promising strategy for activating the resolution of inflammatory lung injury.
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612.|Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612.|Department of Anesthesiology and Intensive Care, Changhai Hospital, Shanghai 200433, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Undergraduate Program, Department of Biology, Washington University in St. Louis, St. Louis, MO 63130; and.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612.|Department of Anesthesiology and Intensive Care, Changhai Hospital, Shanghai 200433, China.
authors.forename: Lulong
authors.identifier: 0000-0001-6787-1837
authors.initials: L
authors.lastname: Bo
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612.|Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612; gchu@uic.edu.|Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612.
authors.forename: Guochang
authors.initials: G
authors.lastname: Hu
mesh_terms: D000072198:ADAM17 Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D055370:Lung Injury / Q000276:immunology / Q000517:prevention & control; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology* / Q000502:physiology; D010587:Phagocytosis; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D000072198:ADAM17 Protein; D018955:CD36 Antigens; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C000606463:Adam17 protein, mouse