An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens

Meliopoulos, Victoria A.; Van de Velde, Lee-Ann; Van de Velde, Nicholas C.; Karlsson, Erik A.; Neale, Geoff; Vogel, Peter; Guy, Cliff; Sharma, Shalini; Duan, Susu; Surman, Sherri L.; Jones, Bart G.; Johnson, Michael D. L.; Bosio, Catharine; Jolly, Lisa; Jenkins, R. Gisli; Hurwitz, Julia L.; Rosch, Jason W.; Sheppard, Dean; Thomas, Paul G.; Murray, Peter J.; Schultz-Cherry, Stacey

crophages, which play a critical role in controlling infections, and the regulation of these responses. Our data identify a pathway by which alveolar epithelial cells normally suppress the anti-microbial activity of alveolar macrophages through a pathway that may involve local activation of TGF-β and subsequent suppression of IFN signaling. In terms of homeostasis, little is known about how type I IFNs control the status of tissue microenvironments. Most work on type I IFN signaling has been associated with anti-viral responses and the regulation of inflammation over the first 18-24 months of life [16] . The implication of our findings is that the lung can tolerate a homeostatic increase in IFN signaling, which provides an advantage against viral spread, but likely comes with 'costs' that are not yet clear. We note a recent study has shown homeostatic IFN-β and IFNAR signaling in the brain has an essential role in suppressing neurodegeneration [53] . Therefore, a more comprehensive understanding of the hitherto unknown tissue-specific homeostatic roles of type I IFN signaling is warranted. During infection, although it would seem that upregulation of β6 would only have a negative impact on the host by limiting the anti-viral response, it could also be important for balancing the inflammatory response by suppressing activated macrophages through a TGF-β-dependent process [2, 5, 15, 45] , initiating wound repair, or by recruiting macrophages to the site of infection. Attempts to address the role of TGF-β in influenza pathogenesis by systemic inhibition resulted in lethal infection [54] . Thus, future studies will focus on inhibiting the β6 integrin at different times post-infection to understand its precise role in viral infection and its potential as a therapeutic target.