Flagellin stimulates protective lung mucosal immunity: role of cathelicidin-related antimicrobial peptide.
TLRs are required for generation of protective lung mucosal immune responses against microbial pathogens. In this study, we evaluated the effect of the TLR5 ligand flagellin on stimulation of antibacterial mucosal immunity in a lethal murine Pseudomonas aeruginosa pneumonia model. The intranasal pretreatment of mice with purified P. aeruginosa flagellin induced strong protection against intratracheal P. aeruginosa-induced lethality, which was attributable to markedly improved bacterial clearance, reduced dissemination, and decreased alveolar permeability. The protective effects of flagellin on survival required TLR5 and were observed even in the absence of neutrophils. Flagellin induced strong induction of innate genes, most notably the antimicrobial peptide cathelicidin-related antimicrobial peptide. Finally, flagellin-induced protection was partially abrogated in cathelicidin-related antimicrobial peptide-deficient mice. Our findings illustrate the profound stimulatory effect of flagellin on lung mucosal innate immunity, a response that might be exploited therapeutically to prevent the development of gram-negative bacterial infection of the respiratory tract.
Yu
Fu-shin
FS
Department of Ophthalmology, Wayne State University, Detroit, MI 48201, USA.
Cornicelli
Matthew D
MD
Kovach
Melissa A
MA
Newstead
Michael W
MW
Zeng
Xianying
X
Kumar
Ashok
A
Gao
Nan
N
Yoon
Sang Gi
SG
Gallo
Richard L
RL
Standiford
Theodore J
TJ
D000281:Administration, Intranasal; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D015153:Blotting, Western; D054804:Cathelicidins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D005408:Flagellin / Q000008:administration & dosage / Q000276:immunology*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D018928:Immunity, Mucosal / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000517:prevention & control; D011552:Pseudomonas Infections / Q000276:immunology / Q000517:prevention & control; D054406:Pseudomonas Vaccines / Q000008:administration & dosage / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D054406:Pseudomonas Vaccines; D051198:Toll-Like Receptor 5; D005408:Flagellin