title: TNF-related apoptosis-inducing ligand (TRAIL) regulates inflammatory neutrophil apoptosis and enhances resolution of inflammation.
abstract: Novel therapeutics targeting neutrophilic inflammation are a major unmet clinical need in acute and chronic inflammation. The timely induction of neutrophil apoptosis is critical for inflammation resolution, and it is thought that acceleration of apoptosis may facilitate resolution at inflammatory sites. We previously demonstrated that a death receptor ligand, TRAIL, accelerates neutrophil apoptosis in vitro. We examined the role of TRAIL in neutrophil-dominant inflammation in WT and TRAIL-deficient mice. TRAIL deficiency did not alter constitutive neutrophil apoptosis, whereas exogenous TRAIL accelerated apoptosis of murine peripheral blood neutrophils. We compared TRAIL-deficient and WT mice in two independent models of neutrophilic inflammation: bacterial LPS-induced acute lung injury and zymosan-induced peritonitis. In both models, TRAIL-deficient mice had an enhanced inflammatory response with increased neutrophil numbers and reduced neutrophil apoptosis. Correction of TRAIL deficiency and supraphysiological TRAIL signaling using exogenous protein enhanced neutrophil apoptosis and reduced neutrophil numbers in both inflammatory models with no evidence of effects on other cell types. These data indicate the potential therapeutic benefit of TRAIL in neutrophilic inflammation.
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, University of Sheffield, Sheffield, UK.
authors.forename: Emmet E
authors.initials: EE
authors.lastname: McGrath
authors.forename: Helen M
authors.initials: HM
authors.lastname: Marriott
authors.forename: Allan
authors.initials: A
authors.lastname: Lawrie
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
authors.forename: David H
authors.initials: DH
authors.lastname: Dockrell
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D007249:Inflammation; D008070:Lipopolysaccharides / Q000633:toxicity; D008171:Lung Diseases / Q000139:chemically induced / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D010538:Peritonitis / Q000276:immunology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D053221:TNF-Related Apoptosis-Inducing Ligand