Loss of epithelial Gq and G11 signaling inhibits TGFβ production but promotes IL-33-mediated macrophage polarization and emphysema

Heterotrimeric guanine nucleotide-binding protein (G protein) signaling links hundreds of G protein-coupled receptors with four G protein signaling pathways. Two of these, one mediated by G(q) and G(11) (G(q/11)) and the other by G(12) and G(13) (G(12/13)), are implicated in the force-dependent activation of transforming growth factor-beta (TGF beta) in lung epithelial cells. Reduced TGF beta activation in alveolar cells leads to emphysema, whereas enhanced TGF beta activation promotes acute lung injury and idiopathic pulmonary fibrosis. Therefore, precise control of alveolar TGF beta activation is essential for alveolar homeostasis. We investigated the involvement of the G(q/11) and G(12/13) pathways in epithelial cells in generating active TGF beta and regulating alveolar inflammation. Mice deficient in both G alpha(q) and G alpha(11) developed inflammation that was primarily caused by alternatively activated (M2-polarized) macrophages, enhanced matrix metalloproteinase 12 (MMP12) production, and age-related alveolar airspace enlargement consistent with emphysema. Mice with impaired G(q/11) signaling had reduced stretch-mediated generation of TGF beta by epithelial cells and enhanced macrophage MMP12 synthesis but were protected from the effects of ventilator-induced lung injury. Furthermore, synthesis of the cytokine interleukin-33 (IL-33) was increased in these alveolar epithelial cells, resulting in the M2-type polarization of alveolar macrophages independently of the effect on TGF beta. Our results suggest that alveolar G(q/11) signaling maintains alveolar homeostasis and likely independently increases TGF beta activation in response to the mechanical stress of the epithelium and decreases epithelial IL-33 synthesis. Together, these findings suggest that disruption of G(q/11) signaling promotes inflammatory emphysema but protects against mechanically induced lung injury.