title: Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense.
abstract: Bacterial pneumonia is an increasing complication of HIV infection and inversely correlates with the CD4(+) lymphocyte count. Interleukin (IL)-17 is a cytokine produced principally by CD4(+) T cells, which induces granulopoiesis via granulocyte colony-stimulating factor (G-CSF) production and induces CXC chemokines. We hypothesized that IL-17 receptor (IL-17R) signaling is critical for G-CSF and CXC chemokine production and lung host defenses. To test this, we used a model of Klebsiella pneumoniae lung infection in mice genetically deficient in IL-17R or in mice overexpressing a soluble IL-17R. IL-17R-deficient mice were exquisitely sensitive to intranasal K. pneumoniae with 100% mortality after 48 h compared with only 40% mortality in controls. IL-17R knockout (KO) mice displayed a significant delay in neutrophil recruitment into the alveolar space, and had greater dissemination of K. pneumoniae compared with control mice. This defect was associated with a significant reduction in steady-state levels of G-CSF and macrophage inflammatory protein (MIP)-2 mRNA and protein in the lung in response to the K. pneumoniae challenge in IL-17R KO mice. Thus, IL-17R signaling is critical for optimal production of G-CSF and MIP-2 and local control of pulmonary K. pneumoniae infection. These data support impaired IL-17R signaling as a potential mechanism by which deficiency of CD4 lymphocytes predisposes to bacterial pneumonia.
authors.affiliation: Louisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ye
authors.forename: F H
authors.initials: FH
authors.lastname: Rodriguez
authors.forename: S
authors.initials: S
authors.lastname: Kanaly
authors.forename: K L
authors.initials: KL
authors.lastname: Stocking
authors.forename: J
authors.initials: J
authors.lastname: Schurr
authors.forename: P
authors.initials: P
authors.lastname: Schwarzenberger
authors.forename: P
authors.initials: P
authors.lastname: Oliver
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: J E
authors.initials: JE
authors.lastname: Shellito
authors.forename: G J
authors.initials: GJ
authors.lastname: Bagby
authors.forename: S
authors.initials: S
authors.lastname: Nelson
authors.forename: K
authors.initials: K
authors.lastname: Charrier
authors.forename: J J
authors.initials: JJ
authors.lastname: Peschon
authors.forename: J K
authors.initials: JK
authors.lastname: Kolls
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D019743:Chemokines, CXC / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D007710:Klebsiella Infections / Q000276:immunology; D007711:Klebsiella pneumoniae / Q000302:isolation & purification; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019743:Chemokines, CXC; C491673:Il17ra protein, mouse; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor