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.

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1+ cells into the liver

“…Yet, a recent study using transcriptome analysis revealed that mRNA expression of GM-CSF and IL-17, but not IL-3, IL-6, IL-11, G-CSF and SCF, is up-regulated by iNKT cells immediately (1 h) after a-GalCer treatment [72], and IL-17 has recently been shown to be secreted by iNKT cells lacking NK1.1 surface expression [73]. Since (i) GM-CSF and IL-17 play a crucial role in granulopoiesis [9,10,[15][16][17][18] and (ii) numbers of Gr-1 1 cells were numerically increased after a-GalCer treatment, we wondered whether increase in liver Gr-1 1 cells following a-GalCer treatment was due to accelerated granulopoiesis. To address this issue, we first examined secretion of GM-CSF and IL-17 after a-GalCer treatment by intracellular cytokine staining.…”

“…GM-CSF can promote granulopoiesis [9,10], and has been implicated in protection against L. monocytogenes infection [74]. IL-17 plays a crucial role in induction of G-CSF [9,10,[15][16][17][18], and has also been implicated in protection against L. monocytogenes infection [67,75]. Therefore, we next examined whether infiltration of Gr-1 1 cells into the liver following a-GalCer treatment is caused by GM-CSF and/or IL-17.…”

“…Numerous cytokines such as GM-CSF, IL-3, IL-6, IL-11, and SCF promote granulopoiesis by themselves and/or in concert with G-CSF [9,10]. G-CSF is indispensable for both steady-state and emergency granulopoiesis [11][12][13][14], and IL-17 regulates G-CSF secretion [9,10,[15][16][17][18]. In addition to Gr-1 1 cells, g/d T cells also participate in early protection against L. monocytogenes infection [19][20][21][22].…”

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…It plays a crucial role in the host defence against bacterial and fungal infection by inducing pro‐inflammatory cytokines and chemokines, recruiting neutrophils, and activating T cells and B cells 1, 2. Mice deficient for IL‐17RA are highly susceptible to Klebsiella pneumoniae 3 and IL‐17‐deficient mice are susceptible to bacterial and fungal infection 4, 5. Interleukin‐17 is also implicated in various inflammatory/autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE), arthritis in IL‐1 receptor antagonist‐deficient (Il1rn –/– ) mice and imiquimod‐induced psoriatic dermatitis in mice 6, 7, 8, 9, 10.…”

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

“…Recently, it has been shown that IL-17 is produced by diverse T-cell subsets, including CD4 1 T cells, CD8 1 T cells, NKT cells and gd T cells [9][10][11][12]. Physiologically, IL-17 plays a pivotal role in protecting the host against certain infectious microorganisms through the recruitment of neutrophils, by increasing the expression of multiple chemokines [13,14]. Furthermore, IL-17 has been implicated in many inflammatory and autoimmune disorders such as colitis, rheumatoid arthritis, and asthma [8,9,14,15].…”