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Abstract
Tumor progression locus 2 (Tpl2) is a serine/threonine kinase that regulates the expression of inflammatory mediators in response to a variety of TLR, cytokine and G-protein-coupled receptors. Tpl2 negatively regulates the expression of host-encoded interferons (IFNs) within hematopoietic cells, however the regulation of antiviral responses by Tpl2 within the target cells of influenza infection, the lung epithelial cells, has not been investigated. We used Nkx2.1-Cre and Sftpc-CreERT2 to drive Tpl2 deletion within pulmonary epithelial cells to delineate epithelial cell-specific functions of Tpl2 during influenza infection. Tpl2 ablation within lung epithelial cells using Nkx2.1-Cre Tpl2fl/- mice caused a significant increase in morbidity, mortality, and pulmonary fibrosis in response to influenza infection. In vitro studies confirmed that Tpl2 constrains both type I and type III IFN responses within the type I airway epithelial cell (AECI) line, LET1, as well as primary type II airway epithelial cells (AECII). Overall, these results implicate Tpl2 in the regulation of early innate responses within pulmonary epithelial cells during influenza infection. Using Sftpc-CreERT2 Tpl2fl/- mice, which require tamoxifen treatment to induce Tpl2 deletion within AECII, we report histopathologic changes in the lungs in cre-recombinase-negative mice treated with tamoxifen intraperitoneally. These changes were noted in distal organs such as the lungs which were characterized by the presence of inflammation within the alveolus, perivascular cuff, vasculature, and pleural cavity, resulting in an inflammatory cell infiltrate. These findings provide a cautionary note that tamoxifen treatment alone leads to histological alterations that may obscure research interpretations and highlights the need for the development of other innovative mouse models for inducible cre-mediated deletion. Collectively, the findings demonstrate that Tpl2 negatively regulates type I and type III IFN production within lung epithelial cells in response to virus sensing in vitro and that Tpl2 ablation within lung epithelial cells is sufficient to leads to dyspnea and pulmonary fibrosis in response to influenza infection.