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

Abstract

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 Gq and G11 (Gq/11) and the other by G12 and G13 (G12/13), are implicated in the force-dependent activation of transforming growth factor-β (TGFβ) in lung epithelial cells. Reduced TGFβ activation in alveolar cells leads to emphysema, whereas enhanced TGFβ activation promotes acute lung injury and idiopathic pulmonary fibrosis. Therefore, precise control of alveolar TGFβ activation is essential for alveolar homeostasis. We investigated the involvement of the Gq/11 and G12/13 pathways in epithelial cells in generating active TGFβ and regulating alveolar inflammation. Mice deficient in both Gαq and Gα11 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 Gq/11 signaling had reduced stretch-mediated generation of TGFβ 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 TGFβ. Our results suggest that alveolar Gq/11 signaling maintains alveolar homeostasis and likely independently increases TGFβ activation in response to the mechanical stress of the epithelium and decreases epithelial IL-33 synthesis. Together, these findings suggest that disruption of Gq/11 signaling promotes inflammatory emphysema but protects against mechanically induced lung injury.

• Authors: Alison E John, Michael R Wilson, Anthony Habgood, Joanne Porte, Amanda L Tatler, Anastasios Stavrou, Gino Miele, Lisa Jolly, Alan J Knox, Masao Takata, Stefan Offermanns, R Gisli Jenkins
• Journal: Science signaling (Sci Signal) Vol. 9 Issue 451 Pg. ra104 (10 25 2016) ISSN: 1937-9145 [Electronic] United States
• PMID: 27811142 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Il33 protein, mouse
• Interleukin-33
• Transforming Growth Factor beta
• Matrix Metalloproteinase 12
• matrix metallopeptidase 12, mouse
• GTP-Binding Protein alpha Subunits, Gq-G11

Topics

• Animals
• Emphysema (genetics, metabolism)
• GTP-Binding Protein alpha Subunits, Gq-G11 (genetics, metabolism)
• Interleukin-33 (genetics, metabolism)
• Macrophages, Alveolar (metabolism)
• Matrix Metalloproteinase 12 (genetics, metabolism)
• Mice
• Mice, Transgenic
• Respiratory Mucosa (metabolism, pathology)
• Signal Transduction
• Transforming Growth Factor beta (genetics, metabolism)
• Ventilator-Induced Lung Injury (genetics, metabolism)