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

John, Alison, E.; Wilson, Michael, R.; Habgood, Anthony; Porte, Joanne; Tatler, Amanda L.; Stavrou, Anastasios; Miele, Gino; Jolly, Lisa; Knox, Alan J.; Takata, Masao; Offermanns, Stefan; Jenkins, R. Gisli

Abstract

Heterotrimeric guanine nucleotide–binding protein (G protein) signaling is a ubiquitous signaling system that links hundreds of G protein–coupled receptors (GPCRs) with four G protein signaling pathways. Two of these pathways, one mediated by Gq and G11 and the other by G12 and G13, 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. Here, we investigated whether the Gq/G11 or G12/G13 pathways in epithelial cells are required to generate TGFβ and suppress alveolar inflammation. Mice deficient in both Gαq and Gα11 developed inflammation primarily due to alternatively activated (M2-polarized) macrophages, enhanced production of matrix metalloprotease 12 (MMP12), and age-related alveolar airspace enlargement consistent with emphysema. We found that mice with impaired Gq/G11 signaling had reduced stretch-mediated generation of TGFβ by epithelial cells and elevated macrophage MMP12 synthesis, but were protected from the effects of ventilator-induced lung injury. Furthermore, synthesis of the pleiotropic 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/G11 signaling maintains alveolar homeostasis and is likely to independently upregulate mechanotransduced epithelial TGFβ activation and downregulate epithelial IL-33 synthesis. Together, these findings suggest that disruption of Gq/G11 signaling promotes inflammatory emphysema, but protects against mechanostransduced lung injury.

Citation

John, A. E., Wilson, M. R., Habgood, A., Porte, J., Tatler, A. L., Stavrou, A., …Jenkins, R. G. (2016). Loss of epithelial Gq and G11 signaling inhibits TGFβ production but promotes IL-33–mediated macrophage polarization and emphysema. Science Signaling, 9(451), Article ra104. https://doi.org/10.1126/scisignal.aad5568

• Journal Article Type: Article
• Acceptance Date: Oct 7, 2016
• Publication Date: Oct 25, 2016
• Deposit Date: Nov 3, 2016
• Publicly Available Date: Nov 3, 2016
• Journal: Science Signaling
• Print ISSN: 1945-0877
• Electronic ISSN: 1937-9145
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 451
• Article Number: ra104
• DOI: https://doi.org/10.1126/scisignal.aad5568
• Public URL: https://nottingham-repository.worktribe.com/output/821767
• Publisher URL: http://stke.sciencemag.org/content/9/451/ra104
• Additional Information: This manuscript has been accepted for publication in Science Signaling. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencesignaling.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS.; ; This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in ; Science Signaling on 25/10/2016, v. 9. DOI:10.1126/scisignal.aad5568.