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 Gqand G11(Gq/11) and the other by G12and 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/11and G12/13pathways in epithelial cells in generating active TGFβ and regulating alveolar inflammation. Mice deficient in both Gαqand Gα11developed 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/11signaling 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/11signaling 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/11signaling promotes inflammatory emphysema but protects against mechanically induced lung injury.
Division of Respiratory Medicine, University of Nottingham, Nottingham, U.K. alison.john@nottingham.ac.uk.
Alison E
AE
John
Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College, London, U.K.
Michael R
MR
Wilson
Division of Respiratory Medicine, University of Nottingham, Nottingham, U.K.
Anthony
A
Habgood
Division of Respiratory Medicine, University of Nottingham, Nottingham, U.K.
Joanne
J
Porte
Division of Respiratory Medicine, University of Nottingham, Nottingham, U.K.
Amanda L
AL
Tatler
Division of Respiratory Medicine, University of Nottingham, Nottingham, U.K.
Anastasios
A
Stavrou
Epistem Ltd., Manchester, U.K.
Gino
G
Miele
Division of Respiratory Medicine, University of Nottingham, Nottingham, U.K.
Lisa
L
Jolly
Division of Respiratory Medicine, University of Nottingham, Nottingham, U.K.
Alan J
AJ
Knox
Department of Anaesthetics, Pain Medicine and Intensive Care, Imperial College, London, U.K.
Masao
M
Takata
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Stefan
S
Offermanns
Division of Respiratory Medicine, University of Nottingham, Nottingham, U.K.
R Gisli
RG
Jenkins
D000818:Animals; D004646:Emphysema / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33 / Q000235:genetics / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism*; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D055397:Ventilator-Induced Lung Injury / Q000235:genetics / Q000378:metabolism
C506535:Il33 protein, mouse; D000067596:Interleukin-33; D016212:Transforming Growth Factor beta; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11