Lung dendritic cells elicited by Fms-like tyrosine 3-kinase ligand amplify the lung inflammatory response to lipopolysaccharide.
BACKGROUND
Strategically located beneath the alveolar epithelial barrier, dendritic cells (DCs) of the lung are centrally involved in the sampling and processing of inhaled antigens. However, the contribution of DCs to acute lung inflammation induced by inhaled bacterial toxins is largely unknown.


OBJECTIVE
To determine the effect of increased lung DC numbers elicited by Fms-like tyrosine kinase-3 ligand (Flt3L) on the acute lung inflammatory response to Escherichia coli lipopolysaccharide (LPS) and Klebsiella pneumoniae infection.


METHODS
Mice were pretreated with Flt3L either in the absence or presence of anti-CD11a antibodies to block the Flt3L-elicited lung DC accumulation or were made transiently neutropenic and then challenged with E. coli LPS or K. pneumoniae.


RESULTS
Flt3L-pretreated mice challenged with LPS responded with drastically increased numbers of both lung parenchymal and alveolar DCs together with an aggravated neutrophilic alveolitis, elevated tumor necrosis factor-alpha and IL-12 levels, and a strongly increased lung permeability compared with LPS- or Flt3L-only-treated mice. Anti-CD11a-mediated blockade of lung DC accumulation significantly attenuated the lung permeability developing in response to LPS, whereas transient neutropenia did not affect lung permeability changes. Finally, Flt3L-pretreated mice responded with increased lung permeability and decreased survival upon infection with K. pneumoniae.


CONCLUSIONS
Lung DCs actively participate in the early inflammatory response to both inhaled bacterial toxins and live bacteria and play a yet unrecognized role in regulating lung barrier integrity.
von Wulffen
Werner
W
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Giessen Lung Center, Giessen, Germany.
Steinmueller
Mirko
M
Herold
Susanne
S
Marsh
Leigh M
LM
Bulau
Patrick
P
Seeger
Werner
W
Welte
Tobias
T
Lohmeyer
Jürgen
J
Maus
Ulrich A
UA
D000818:Animals; D002452:Cell Count; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects*; D004926:Escherichia coli; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000378:metabolism; D007710:Klebsiella Infections / Q000378:metabolism / Q000473:pathology*; D007711:Klebsiella pneumoniae; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D054426:Chemokine CXCL2; D053765:Interleukin-12 Subunit p35; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C084881:flt3 ligand protein