Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation.
Cystic fibrosis (CF) is characterized by an excessive neutrophilic inflammatory response within the airway as a result of defective cystic fibrosis transmembrane receptor (CFTR) expression and function. Interleukin-17A induces airway neutrophilia and mucin production associated with Pseudomonas aeruginosa colonization, which is associated with the pathophysiology of cystic fibrosis. The objectives of this study were to use the preclinical murine model of cystic fibrosis lung infection and inflammation to investigate the role of IL-17 in CF lung pathophysiology and explore therapeutic intervention with a focus on IL-17. Cftr-deficient mice (CF mice) and wild-type mice (WT mice) infected with P. aeruginosa had robust IL-17 production early in the infection associated with a persistent elevated inflammatory response. Intratracheal administration of IL-17 provoked a neutrophilic response in the airways of WT and CF animals which was similar to that observed with P. aeruginosa infection. The neutralization of IL-17 prior to infection significantly improved the outcomes in the CF mice, suggesting that IL-17 may be a therapeutic target. We demonstrate in this report that the pathophysiological contribution of IL-17 may be due to the induction of chemokines from the epithelium which is augmented by a deficiency of Cftr and ongoing inflammation. These studies demonstrate the in vivo contribution of IL-17 in cystic fibrosis lung disease and the therapeutic validity of attenuating IL-17 activity in cystic fibrosis.
San Antonio Military Medical Center, Department of Pediatrics, JBSA Fort Sam Houston, Texas, USA.
Daniel
D
Hsu
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
Patricia
P
Taylor
Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
Dave
D
Fletcher
Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
Rolf
R
van Heeckeren
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
Jean
J
Eastman
Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
Anna
A
van Heeckeren
Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
Pamela
P
Davis
Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA.
James F
JF
Chmiel
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
Eric
E
Pearlman
Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA Tracey.Bonfield@case.edu.
Tracey L
TL
Bonfield
D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D008171:Lung Diseases / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000188:drug therapy / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000378:metabolism*
D018925:Chemokines; D020381:Interleukin-17; D019005:Cystic Fibrosis Transmembrane Conductance Regulator