Viral infections are associated with a majority of asthma exacerbations in both children and adults. In such instances, virally-induced asthma exacerbations most often occur in the setting of underlying pulmonary allergic inflammation. Respiratory syncytial virus (RSV) infections cause a significant number of asthma exacerbations in both children and adults; however, the mechanisms by which RSV infection leads to worsening of asthma symptoms and decreased lung function are not fully defined. Our preliminary data suggests that interleukin (IL)-17A is a critical regulator of RSV-induced airway responsiveness (AR) and mucus expression. In a mouse model, we found that RSV challenge in the setting of allergic lung disease resulted in increased AR and augmented airway mucus expression, compared to mice that were not challenged with RSV during allergic inflammation. The heightened AR and mucus expression in the mice that were RSV-challenged in the presence of allergic inflammation did not correlate with the lung expression of IL-13, a cytokine that is proposed to be central regulator of AR and airway mucus expression, but instead was associated with significantly increased lung IL-17A expression. In contrast, RSV challenge in the absence of allergic lung inflammation did not result in AR, mucus expression, or detectable IL-17A levels. In this proposal, we hypothesize that IL-17A produced by the combination of allergic inflammation and RSV challenge mediates RSV-induced augmented AR and airway mucus. The long-term goals of this proposal are to: 1) fully define the role of IL-17A in the heightened AR and airway mucus expression that results when RSV challenge occurs during ongoing allergic airway inflammation, and 2) define the role of prostaglandin E2 (PGE2) produced by ongoing allergic inflammation in RSV-induced lung IL-23 expression. IL-23 is a cytokine made by dendritic cells which is critical to the expansion and maintenance of IL-17A producing T cells, now known as Th17 cells. Defining the role of IL-17A in the immunobiology of virally-mediated AR and mucus induction may result in novel targets for drug development. ? ? ?
| Toki, Shinji; Goleniewska, Kasia; Huckabee, Matthew M et al. (2013) PGI? signaling inhibits antigen uptake and increases migration of immature dendritic cells. J Leukoc Biol 94:77-88 |
| Newcomb, Dawn C; Boswell, Madison G; Sherrill, Taylor P et al. (2013) IL-17A induces signal transducers and activators of transcription-6-independent airway mucous cell metaplasia. Am J Respir Cell Mol Biol 48:711-6 |
| Sevin, Carla M; Newcomb, Dawn C; Toki, Shinji et al. (2013) Deficiency of gp91phox inhibits allergic airway inflammation. Am J Respir Cell Mol Biol 49:396-402 |
| Newcomb, Dawn Catherine; Boswell, Madison G; Reiss, Sara et al. (2013) IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation. Thorax 68:717-23 |
| Lotz, Matthew T; Moore, Martin L; Peebles Jr, R Stokes (2013) Respiratory syncytial virus and reactive airway disease. Curr Top Microbiol Immunol 372:105-18 |
| Newcomb, Dawn C; Peebles Jr, R Stokes (2013) Th17-mediated inflammation in asthma. Curr Opin Immunol 25:755-60 |
| Zhou, Weisong; Dowell, Dustin R; Huckabee, Matthew M et al. (2012) Prostaglandin I2 signaling drives Th17 differentiation and exacerbates experimental autoimmune encephalomyelitis. PLoS One 7:e33518 |
| Newcomb, Dawn C; Boswell, Madison G; Huckabee, Matthew M et al. (2012) IL-13 regulates Th17 secretion of IL-17A in an IL-10-dependent manner. J Immunol 188:1027-35 |
| Dorris, Stacy L; Peebles Jr, R Stokes (2012) PGI2 as a regulator of inflammatory diseases. Mediators Inflamm 2012:926968 |
| Lotz, Matthew T; Peebles Jr, R Stokes (2012) Mechanisms of respiratory syncytial virus modulation of airway immune responses. Curr Allergy Asthma Rep 12:380-7 |
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