title: TLR4 through IFN-β promotes low molecular mass hyaluronan-induced neutrophil apoptosis.
abstract: Intratracheal administration of low molecular mass (LMM) hyaluronan (200 kDa) results in greater neutrophil infiltration in the lungs of TLR4(-/-) mice compared with that in wild-type mice. In general, enhanced neutrophil infiltration in tissue is due to cell influx; however, neutrophil apoptosis also plays an important role. We have assessed the effects of TLR4 in the regulation of neutrophil apoptosis in response to administration of LMM hyaluronan. We found that apoptosis of inflammatory neutrophils is impaired in TLR4(-/-) mice, an effect that depends upon the IFN-β-mediated TRAIL/TRAILR system. IFN-β levels were decreased in LMM hyaluronan-treated TLR4-deficient neutrophils. The treatment of inflammatory neutrophils with IFN-β enhanced the levels of TRAIL and TRAILR 2. LMM hyaluronan-induced inflammatory neutrophil apoptosis was substantially prevented by anti-TRAIL neutralizing mAb. We conclude that decreased IFN-β levels decrease the activity of the TRAIL/TRAILR system in TLR4-deficient neutrophils, leading to impaired apoptosis of neutrophils and resulting in abnormal accumulation of neutrophils in the lungs of LMM hyaluronan-treated mice. Thus, TLR4 plays a novel homeostatic role in noninfectious lung inflammation by accelerating the elimination of inflammatory neutrophils.
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Shaw-Wei
authors.initials: SW
authors.lastname: Leu
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
authors.forename: Yili
authors.initials: Y
authors.lastname: Zhao
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Aviva
authors.initials: A
authors.lastname: Shiedlin
authors.forename: Charlie
authors.initials: C
authors.lastname: Xiang
authors.forename: Huahao
authors.initials: H
authors.lastname: Shen
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Quinn
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hales
authors.forename: Hang
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D006706:Homeostasis / Q000276:immunology; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000502:physiology*; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000737:chemistry / Q000502:physiology; D016899:Interferon-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008970:Molecular Weight; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D006820:Hyaluronic Acid