Cystic fibrosis is caused by mutated cystic fibrosis 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 post-apoptotic necrosis and actively suppresses release of a variety of pro-inflammatory 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 impaired 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 to 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 pro-inflammatory consequences, because apoptotic cells enhance IL-8 release by these cells, but not by wild-type controls. Therefore, in cystic fibrosis, dysregulated efferocytosis may lead to accumulation of apoptotic cells, impaired regulation of the inflammatory response, and ultimately may suggest a new therapeutic target. Key words: Efferocytosis, Rho GTPase, inflammation, epithelial cells.
"Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator Inhibits Phagocytosis of Apoptotic Cells with Pro-inflammatory Consequences"
Am J Physiol Lung Cell Mol Physiol. 2009 Jul 24; Vandivier RW, Richens TR, Horstmann SA, Decathelineau AM, Ghosh M, Reynolds SD, Xiao YQ, Riches DW, Plumb JD, Vachon E, Downey GP, Henson PM
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