title: Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease.
abstract: Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.
authors.affiliation: COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, 80262, USA.
authors.forename: Konosuke
authors.initials: K
authors.lastname: Morimoto
authors.forename: William J
authors.initials: WJ
authors.lastname: Janssen
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: McPhillips
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Borges
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Xiao
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kench
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.forename: R William
authors.initials: RW
authors.lastname: Vandivier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018955:CD36 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D019169:Jurkat Cells; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009000:Monocytes / Q000166:cytology; D010587:Phagocytosis / Q000502:physiology; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008246:Lysophospholipids; D008565:Membrane Proteins; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid