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

Why is the lung macrophage population different in the β6 KO mice? The αVβ6 integrin is expressed at low amounts in healthy adult tissue but is rapidly upregulated during development and in response to injury and inflammation [30] . Once expressed, β6 activates latent TGF-β1 by binding to the RGD motif in the latency-associated peptide (LAP) [10, 55] . Upon activation, TGF-β1 regulates a variety of genes associated with the immune response and pulmonary fibrosis and is thought to negatively restrict inflammation in macrophages through an unknown mechanism [45] . However, systemic inhibition of all TGF-β isoforms by a broadly neutralizing antibody led to lethal influenza infection [54] suggesting that the role of TGF-β during infection may be complex and depend on both the cellular milieu and TGF-β isoform. Recent work has shown that the pulmonary microenvironment dictates the behavior of alveolar macrophages to a greater extent than the origin of the macrophages [42] . Based on our studies we propose that in the lung microenvironment, upregulation of the β6 integrin leads to localized activation of TGF-β1 that negatively regulates alveolar macrophages leading to decreased type I IFN activity in the microenvironment through an as yet undefined mechanism that will require further molecular investigation. An important extension of this model is that influenza viruses themselves activate latent TGF-β during infection [56] and global inhibition of TGF-β during infection is lethal, suggesting an important role in protection from influenza [54] . Therefore, it will be important to be able to experimentally segregate the host-versus virus-specific TGF-β processing events in mice expressing or lacking β6 integrin.