title: FMS-like tyrosine kinase 3 ligand treatment of mice aggravates acute lung injury in response to Streptococcus pneumoniae: role of pneumolysin.
abstract: FMS-like tyrosine kinase-3 ligand (Flt3L) is a dendritic cell (DC) growth and differentiation factor with potential in antitumor therapies and antibacterial immunization strategies. However, the effect of systemic Flt3L treatment on lung-protective immunity against bacterial infection is incompletely defined. Here, we examined the impact of deficient (in Flt3L knockout [KO] mice), normal (in wild-type [WT] mice), or increased Flt3L availability (in WT mice pretreated with Flt3L for 3, 5, or 7 days) on lung DC subset profiles and lung-protective immunity against the major lung-tropic pathogen, Streptococcus pneumoniae. Although in Flt3L-deficient mice the numbers of DCs positive for CD11b (CD11b(pos) DCs) and for CD103 (CD103(pos) DCs) were diminished, lung permeability, a marker of injury, was unaltered in response to S. pneumoniae. In contrast, WT mice pretreated with Flt3L particularly responded with increased numbers of CD11b(pos) DCs and with less pronounced numbers of CD103(pos) DCs and impaired bacterial clearance and with increased lung permeability following S. pneumoniae challenge. Notably, infection of Flt3L-pretreated mice with S. pneumoniae lacking the pore-forming toxin, pneumolysin (PLY), resulted in substantially less lung CD11b(pos) DCs activation and reduced lung permeability. Collectively, this study establishes that Flt3L treatment enhances the accumulation of proinflammatory activated lung CD11b(pos) DCs which contribute to acute lung injury in response to PLY released by S. pneumoniae.
authors.affiliation: Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Brumshagen
authors.forename: Regina
authors.initials: R
authors.lastname: Maus
authors.forename: Andrea
authors.initials: A
authors.lastname: Bischof
authors.forename: Bianca
authors.initials: B
authors.lastname: Ueberberg
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bohling
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
authors.forename: Abiodun D
authors.initials: AD
authors.lastname: Ogunniyi
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Maus
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000628:therapy; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*; D013301:Streptolysins / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D039481:CD11b Antigen; D008024:Ligands; D008565:Membrane Proteins; D013301:Streptolysins; C084881:flt3 ligand protein; C032290:plY protein, Streptococcus pneumoniae