Interleukin-17 (IL-17) is a cytokine produced mainly by T cell lineages that plays a key
role in regulation of neutrophil responses. Given the importance of neutrophils in the immune response directed against extracellular pathogens, it is no surprise that IL-17 is important in host defense against a multitude of pathogens. Importantly, however, neutrophils also have been shown to play a role in several immunopathological conditions, including acute lung injury. In this dissertation, we evaluate the role that IL-17 plays in the immunopathology of influenza infection. We show here that IL-17 is produced as early as day 2 following influenza challenge, and that this expression is sustained throughout the first week of infection. Further, we identify γδ T cells as at least one important source of IL-17 in response to influenza. We also demonstrate that loss of IL-17 receptor A (IL-17RA) signaling results in a profound decrease in neutrophil recruitment to the lung following influenza challenge. This decrease in neutrophils results in substantially less inflammation and lung injury, as well as higher survival rates. Additionally, there is only a moderate impact on viral clearance and T cell responses. Further, we detail similar findings in a non-infectious aspiration model of acute lung injury. Taken together, this data suggests that IL-17 signaling may be a key event, and intriguing therapeutic target, in the pathogenesis of acute lung injury.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08062009-211958 |
| Date | 10 August 2009 |
| Creators | Crowe, Christopher R |
| Contributors | Andrea Gambotto, Gerard Nau, Ted Ross, Prabir Ray, Jay Kolls, MD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08062009-211958/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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