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

What could be different about the β6 KO lung microenvironment? β6 integrin is the primary way to endogenously activate transforming growth factor-β (TGF-β) in the lung, which is known to restrain AM activity [16, 45] . Thus, we next asked if the altered macrophage phenotype in the β6 KO mice was TGF-β1 dependent. As expected, endogenous lung TGF-β1 activity was reduced in β6 KO mice as compared to WT (Fig 7A) . To test the hypothesis that reduced TGF-β1 activity contributed to the altered lung microenvironment of β6 KO mice, we intranasally administered exogenous TGF-β1 to WT and β6 KO mice every other day for 3 weeks ( Fig 7B) as described [46] . β6 KO mice treated with TGF-β1 had increased numbers of CD11c +-CD11bmacrophages ( Fig 7C, quantification Fig 7D) , partially reversing the CD11c + CD11b + phenotype, and were no longer protected from influenza infection ( Fig 7E) suggesting that the loss of β6-mediated TGF-β1activation is important for both protection and the 'activated' macrophage phenotype.