title: Modulation of FLT3 signaling targets conventional dendritic cells to attenuate acute lung injury.
abstract: Conventional dendritic cells (cDCs) have been reported to participate in the pathophysiology of acute lung injury (ALI). Fms-like tyrosine kinase 3 (FLT3) signaling represents a highly specific pathway for the manipulation of cDCs in vivo. The purpose of this study was to clarify the effect of FLT3 signaling on the accumulation and maturation of pulmonary cDCs, and whether inhibition of FLT3 signaling may attenuate acute lung inflammation and lung injury. C57BL/6 mice were pretreated with FLT3-ligand (FLT3L) and lestaurtinib separately for five consecutive days. A murine model of ALI was subsequently generated by intra-tracheal instillation of lipopolysaccharide (LPS) and lung specimens were harvested 24 h later. Flow cytometry was conducted to measure the accumulation and maturation of pulmonary cDCs. IL-6, IFN-γ, IL-4, MPO activity and transcription factor T-bet/GATA-3 mRNA ratio were quantified to evaluate lung inflammation. Lung injury was estimated by lung wet weight/body weight ratio (LWW/BW) and histopathological analysis. LPS challenge resulted in rapid accumulation and maturation of pulmonary cDCs. FLT3L pretreatment further stimulated the accumulation and maturation of pulmonary cDCs, leading to a markedly increased LWW/BW and aggravated lung histopathology. Meanwhile, lung MPO activity, T-bet/GATA-3 mRNA ratio and concentrations of IL-6 and IFN-γ were elevated by FLT3L administration. In contrast, lestaurtinib pretreatment inhibited the accumulation and maturation of pulmonary cDCs, leading to a significantly decreased LWW/BW and improved lung histopathology. Lestaurtinib administration also suppressed lung MPO activity, T-bet/GATA-3 mRNA ratio and production of IL-6 and IFN-γ. Our findings show that FLT3 signaling ameliorates ALI by regulating the accumulation and maturation of pulmonary cDCs, suggesting an innovative pharmacotherapy for ALI.
authors.affiliation: Department of Critical Care Medicine, Zhong-Da Hospital, Southeast University, Nanjing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
authors.forename: Hong-Li
authors.initials: HL
authors.lastname: He
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Lu
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Qiu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D001835:Body Weight; D002227:Carbazoles / Q000008:administration & dosage / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D005663:Furans; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000008:administration & dosage / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D002227:Carbazoles; D016207:Cytokines; D005663:Furans; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C119379:lestaurtinib; D009195:Peroxidase; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3