title: Dysfunctional cystic fibrosis transmembrane conductance regulator inhibits phagocytosis of apoptotic cells with proinflammatory consequences.
abstract: Cystic fibrosis (CF) is caused by mutated CF transmembrane conductance regulator (CFTR) and is characterized by robust airway inflammation and accumulation of apoptotic cells. Phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, because it prevents postapoptotic necrosis and actively suppresses release of a variety of proinflammatory mediators, including IL-8. Because CF is associated with accumulation of apoptotic cells, inappropriate levels of IL-8, and robust inflammation, we sought to determine whether CFTR deficiency specifically impairs efferocytosis and its regulation of inflammatory mediator release. Here we show that CFTR deficiency directly interferes with efferocytosis by airway epithelium, an effect that is not due to altered binding of apoptotic cells to epithelial cells or altered expression of efferocytosis receptors. In contrast, expression of RhoA, a known negative regulator of efferocytosis, is substantially increased in CFTR-deficient cells, and inhibitors of RhoA or its downstream effector Rho kinase normalize efferocytosis in these cells. Impaired efferocytosis appears to be mediated through an amiloride-sensitive ion channel, because amiloride restores phagocytic competency in CFTR-deficient cells. Finally, ineffective efferocytosis in CFTR-deficient cells appears to have proinflammatory consequences, because apoptotic cells enhance IL-8 release by these cells, but not by wild-type controls. Therefore, in CF, dysregulated efferocytosis may lead to accumulation of apoptotic cells and impaired regulation of the inflammatory response and, ultimately, may suggest a new therapeutic target.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Univ. of Colorado Denver, Research Bldg. 2, 12700 E. 19th Ave. Box C272, Aurora, CO 80045, USA. Bill.Vandivier@ucdenver.edu
authors.forename: R William
authors.initials: RW
authors.lastname: Vandivier
authors.forename: Tiffany R
authors.initials: TR
authors.lastname: Richens
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Horstmann
authors.forename: Aimee M
authors.initials: AM
authors.lastname: deCathelineau
authors.forename: Moumita
authors.initials: M
authors.lastname: Ghosh
authors.forename: Susan D
authors.initials: SD
authors.lastname: Reynolds
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Xiao
authors.forename: David W
authors.initials: DW
authors.lastname: Riches
authors.forename: Jonathan
authors.initials: J
authors.lastname: Plumb
authors.forename: Eric
authors.initials: E
authors.lastname: Vachon
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
mesh_terms: D000199:Actins / Q000378:metabolism; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis; D017452:Receptors, IgG / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D022502:Stress Fibers; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; C080568:Fc gamma receptor IIA; D018836:Inflammation Mediators; D016209:Interleukin-8; D017452:Receptors, IgG; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000584:Amiloride; D020742:rhoA GTP-Binding Protein