BibTex format
@article{Wilson:2016:10.1126/scisignal.aad5568,
author = {Wilson, MR and Takata, M and John, AE and Habgood, A and Porte, J and Tatler, AL and Stavrou, A and Miele, G and Jolly, L and Knox, AJ and Offermanns, S and Jenkins, RG},
doi = {10.1126/scisignal.aad5568},
journal = {Science Signaling},
pages = {1--17},
title = {Loss of epithelial Gq and G11 signaling inhibits TGFβ production but promotes IL-33–mediated macrophage polarization and emphysema},
url = {http://dx.doi.org/10.1126/scisignal.aad5568},
volume = {9},
year = {2016}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Heterotrimeric guanine nucleotide–binding protein (G protein) signaling links hundreds of Gprotein–coupled receptors (GPCRs) 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 inthe force-dependent activation of transforming growth factor–β (TGFβ) in lung epithelialcells. Reduced TGFβ activation in alveolar cells leads to emphysema, whereas enhancedTGFβ activation promotes acute lung injury and idiopathic pulmonary fibrosis. Therefore,precise control of alveolar TGFβ activation is essential for alveolar homeostasis. Here, weinvestigated the involvement of the Gq/11and G12/13 pathways in epithelial cells in generatingactive TGFβ and regulating alveolar inflammation. Mice deficient in both Gαq and Gα11developed inflammation that was primarily caused by alternatively activated (M2-polarized)macrophages, enhanced matrix metalloprotease 12 (MMP12) production, and age-relatedalveolar airspace enlargement consistent with emphysema. Mice with impaired Gq/11signaling had reduced stretch-mediated generation of TGFβ by epithelial cells and enhancedmacrophage MMP12 synthesis, but were protected from the effects of ventilator-induced lunginjury. Furthermore, synthesis of the cytokine interleukin-33 (IL-33) was increased in thesealveolar epithelial cells, resulting in the M2-type polarization of alveolar macrophages independently of the effect on TGFβ. Our results suggest that alveolar Gq/11 signalingmaintains alveolar homeostasis, and likely independently increases TGFβ activation inresponse to mechanical stress of the epithelium and decreases epithelial IL-33 synthesis.Together, these findings suggest that disruption of Gq/11 signaling promotes inflammatoryemphysema but protects against mechanically induced lung injury.
AU - Wilson,MR
AU - Takata,M
AU - John,AE
AU - Habgood,A
AU - Porte,J
AU - Tatler,AL
AU - Stavrou,A
AU - Miele,G
AU - Jolly,L
AU - Knox,AJ
AU - Offermanns,S
AU - Jenkins,RG
DO - 10.1126/scisignal.aad5568
EP - 17
PY - 2016///
SN - 1945-0877
SP - 1
TI - Loss of epithelial Gq and G11 signaling inhibits TGFβ production but promotes IL-33–mediated macrophage polarization and emphysema
T2 - Science Signaling
UR - http://dx.doi.org/10.1126/scisignal.aad5568
UR - https://stke.sciencemag.org/content/9/451/ra104/
UR - http://hdl.handle.net/10044/1/42242
VL - 9
ER -
Critical care involves the care of the sickest patients in the hospital. Critically ill patients have usually been through a significant insult to their body (such as trauma, infection, burn) and have developed organ failure and require life-support. Critical Care is the largest theme bringing together clinicians and scientists from diverse backgrounds and includes collaborative research from hospitals throughout north-west London. Investigations range from evaluating biological mechanisms of organ failure through to the development of innovative technologies which allow the short-term and long-term support and recovery of organs.