Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense.
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.
Ye
P
P
Louisiana State University Health Sciences Gene Therapy Program, Section of Pulmonary/Critical Care Medicine, New Orleans, LA 70112, USA.
Rodriguez
F H
FH
Kanaly
S
S
Stocking
K L
KL
Schurr
J
J
Schwarzenberger
P
P
Oliver
P
P
Huang
W
W
Zhang
P
P
Zhang
J
J
Shellito
J E
JE
Bagby
G J
GJ
Nelson
S
S
Charrier
K
K
Peschon
J J
JJ
Kolls
J K
JK
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
D019743:Chemokines, CXC; C491673:Il17ra protein, mouse; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor