G protein subunit Gγ13-mediated signaling pathway is critical to the inflammation resolution and functional recovery of severely injured lungs
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eLife assessment
This in principle useful study suggests that the G-protein subunit Gng13 is required for limiting injury and inflammation following H1N1 influenza infection via anti-inflammatory effects from ectopic tuft cells. There appears to be support for Gng13 helping to limit influenza injury in the transgenic mouse models used here, but evidence for these effects being mediated by tuft cells is incomplete, giving conflicting data from mice that lack tuft cells entirely.
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Abstract
Tuft cells are a group of rare epithelial cells that can detect pathogenic microbes and parasites. Many of these cells express signaling proteins initially found in taste buds. It is, however, not well understood how these taste signaling proteins contribute to the response to the invading pathogens or to the recovery of injured tissues. In this study, we conditionally nullified the signaling G protein subunit Gγ13 and found that the number of ectopic tuft cells in the injured lung was reduced following the infection of the influenza virus H1N1. Furthermore, the infected mutant mice exhibited significantly larger areas of lung injury, increased macrophage infiltration, severer pulmonary epithelial leakage, augmented pyroptosis and cell death, greater bodyweight loss, slower recovery, worsened fibrosis and increased fatality. Our data demonstrate that the Gγ13-mediated signal transduction pathway is critical to tuft cells-mediated inflammation resolution and functional repair of the damaged lungs.To our best knowledge, it is the first report indicating subtype-specific contributions of tuft cells to the resolution and recovery.
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eLife assessment
This in principle useful study suggests that the G-protein subunit Gng13 is required for limiting injury and inflammation following H1N1 influenza infection via anti-inflammatory effects from ectopic tuft cells. There appears to be support for Gng13 helping to limit influenza injury in the transgenic mouse models used here, but evidence for these effects being mediated by tuft cells is incomplete, giving conflicting data from mice that lack tuft cells entirely.
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Reviewer #1 (Public Review):
Li et al. report here on the expression of a G-protein subunit Gng13 in ectopic tuft cells that develop after severe pulmonary injury in mice. By deleting this gene in ectopic tuft cells as they arise, the authors observed worsened lung injury and greater inflammation after influenza infection, as well as a decrease in the overall number of ectopic tuft cells. This was in stark contrast to the deletion of Trpm5, a cation channel generally thought to be required for all functional gustatory signaling in tuft cells, where no phenotype is observed. Strengths here include a thorough assessment of lung injury via a number of different techniques. Weaknesses are notable: confusingly, these findings are at odds with reports from other groups demonstrating no obvious phenotype upon influenza infection in mice …
Reviewer #1 (Public Review):
Li et al. report here on the expression of a G-protein subunit Gng13 in ectopic tuft cells that develop after severe pulmonary injury in mice. By deleting this gene in ectopic tuft cells as they arise, the authors observed worsened lung injury and greater inflammation after influenza infection, as well as a decrease in the overall number of ectopic tuft cells. This was in stark contrast to the deletion of Trpm5, a cation channel generally thought to be required for all functional gustatory signaling in tuft cells, where no phenotype is observed. Strengths here include a thorough assessment of lung injury via a number of different techniques. Weaknesses are notable: confusingly, these findings are at odds with reports from other groups demonstrating no obvious phenotype upon influenza infection in mice lacking the transcription factor Pou2f3, which is essential for all tuft cell specification and development. The authors speculate that heterogeneity within nascent tuft cell populations, specifically the presence of pro- and anti-inflammatory tuft cells, may explain this difference, but they do not provide any data to support this idea.
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Reviewer #2 (Public Review):
Summary:
The study by Li et al. aimed to demonstrate the role of the G𝛾13-mediated signal transduction pathway in tuft cell-driven inflammation resolution and repairing injured lung tissue. The authors showed a reduced number of tuft cells in the parenchyma of G𝛾13 null lungs following viral infection. Mice with a G𝛾13 null mutation showed increased lung damage and heightened macrophage infiltration when exposed to the H1N1 virus. Their further findings suggested that lung inflammation resolution, epithelial barrier, and fibrosis were worsened in G𝛾13 null mutants.Strengths:
The beautiful immunostaining findings do suggest that the number of tuft cells is decreased in Gr13 null mutants.Weaknesses:
The description of phenotypes, and the approaches used to measure the phenotypes are problematic. Rigorous …Reviewer #2 (Public Review):
Summary:
The study by Li et al. aimed to demonstrate the role of the G𝛾13-mediated signal transduction pathway in tuft cell-driven inflammation resolution and repairing injured lung tissue. The authors showed a reduced number of tuft cells in the parenchyma of G𝛾13 null lungs following viral infection. Mice with a G𝛾13 null mutation showed increased lung damage and heightened macrophage infiltration when exposed to the H1N1 virus. Their further findings suggested that lung inflammation resolution, epithelial barrier, and fibrosis were worsened in G𝛾13 null mutants.Strengths:
The beautiful immunostaining findings do suggest that the number of tuft cells is decreased in Gr13 null mutants.Weaknesses:
The description of phenotypes, and the approaches used to measure the phenotypes are problematic. Rigorous investigation of the mouse lung phenotypes is needed to draw meaningful conclusions. -