Expression of the human integrin β6 subunit in alveolar type II cells and bronchiolar epithelial cells reverses lung inflammation in β6 knockout mice

Inactivation of the integrin beta 6 subunit gene in mice resulted in an unexpected phenotype-functionally significant inflammation of the skin and lungs. These findings suggested a role for ligation of the alpha v beta 6 integrin on epithelial cells in downregulating epithelial inflammation. However, the results of gene inactivation could have been due to inactivation of adjacent genes and provided no information about the role of this integrin in specific populations of epithelial cells. In the current study, we used transgenic mice constitutively expressing the human beta 6 subunit in alveolar type II cells and bronchiolar epithelial cells to examine directly the significance of alpha v beta 6 in these cells. Expression of this transgene largely inhibited the increases in airspace lymphocytes and macrophages and the lymphocyte and macrophage activation caused by inactivation of the beta 6 subunit gene, and reduced the peribronchial and perivascular accumulations of lymphocytes. In the genetically mixed mice used for this study, we identified airway eosinophilia as an additional effect of beta 6 inactivation. This effect was also partially inhibited by limited expression of the human transgene. These results definitively identify a role for distal lung epithelial alpha v beta 6 in downregulating pulmonary inflammation and suggest that interventions augmenting beta 6 expression or function in these cells could influence the course of inflammatory lung diseases.