Bacterial pneumonia is an important clinical problem and host defense mechanisms against pneumonia are not fully understood. Preliminary data from our laboratory using a murine model of Klebsiella pneumoniae infection has shown that bacterial deposition in the lung results in the release of the T-cell derived cytokines IL-17A and IL-17F, both of which can mediate neutrophil recruitment into the lung. Moreover, we have shown that signaling through the IL-17 receptor is critical for optimal granulocyte-colony stimulating factor (G-CSF) and both Gro-alpha and macrophage inflammatory protein 2 (MIP-2) production in the lung which are critical for granulopoeisis and neutrophil chemotaxis respectively in this model. Furthermore, preliminary data using both in vitro bone marrow derived dendritic cells (DC) and T-cell co-cultures as well as in our experimental model of pneumoniae in vivo has demonstrated that host release of these lymphocyte-derived IL-17 family members is dependent on recognition of the organism by Toll-like receptor 4 (presumably on both alveolar macrophages and lung dendritic cells) and the subsequent production of IL-23 (a novel heterodimeric cytokine composed of a unique p19 subunit and the p40 subunit of IL-12) by these cell populations which signal to T-cell to produce IL-17. This data allows us to propose an experimental hypothesis that both TLR4 and IL-23 are required for the production of IL-17A and IL-17F in the lung and that IL-17R signaling by lung parenchymal cells is critical for host defense against Klebsiella pneumoniae. We will test this hypothesis with the following Specific Aims: 1. Our hypothesis predicts that TLR4 on lung DCs and alveolar macrophages is critical for pulmonary production of IL-23 and IL-17 in response to experimental K. pneumoniae infection. 2. Our hypothesis predicts that IL-23 is required for the production of IL-17A and IL-17F, G-CSF and optimal CXC chemokine production and subsequent neutrophil recruitment in response to experimental K. pneumoniae infection. 3. Our hypothesis predicts that IL-17R signaling by lung parenchymal cells is required for production of G-CSF and optimal CXC chemokine production and subsequent neutrophil recruitment in response to experimental K. pneumoniae infection.
Robinson, Keven M; Lee, Benjamin; Scheller, Erich V et al. (2015) The role of IL-27 in susceptibility to post-influenza Staphylococcus aureus pneumonia. Respir Res 16:10 |
Garg, Abhishek V; Amatya, Nilesh; Chen, Kong et al. (2015) MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation. Immunity 43:475-87 |
Manni, M L; Trudeau, J B; Scheller, E V et al. (2014) The complex relationship between inflammation and lung function in severe asthma. Mucosal Immunol 7:1186-98 |
Pociask, Derek A; Scheller, Erich V; Mandalapu, Sivanarayana et al. (2013) IL-22 is essential for lung epithelial repair following influenza infection. Am J Pathol 182:1286-96 |
Wozniak, Karen L; Hardison, Sarah E; Kolls, Jay K et al. (2011) Role of IL-17A on resolution of pulmonary C. neoformans infection. PLoS One 6:e17204 |
Qin, Shulin; Alcorn, John F; Craigo, Jodi K et al. (2011) Epigallocatechin-3-gallate reduces airway inflammation in mice through binding to proinflammatory chemokines and inhibiting inflammatory cell recruitment. J Immunol 186:3693-700 |
Kudva, Anupa; Scheller, Erich V; Robinson, Keven M et al. (2011) Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice. J Immunol 186:1666-1674 |
Pociask, Derek A; Chen, Kong; Choi, Sun Mi et al. (2011) ?? T cells attenuate bleomycin-induced fibrosis through the production of CXCL10. Am J Pathol 178:1167-76 |
Mitsdoerffer, Meike; Lee, Youjin; Jager, Anneli et al. (2010) Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc Natl Acad Sci U S A 107:14292-7 |
Alcorn, John F; Crowe, Christopher R; Kolls, Jay K (2010) TH17 cells in asthma and COPD. Annu Rev Physiol 72:495-516 |
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