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Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE261794 | GEO | 2024/08/12

REPOSITORIES: GEO

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Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration [RNA-seq]

2024-08-12 | GSE218386 | GEO

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration [scRNA-Seq]

Project description:Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT2 and AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing (scRNA-seq) datasets of human interstitial lung disease, we found that Interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ epithelial cells and basaloid cells. Stimulation of AT2 cells and distal airway epithelial cells with IL11 or TGFβ1 caused epithelial-to-mesenchymal transition (EMT), induced extracellular matrix (ECM) production, increased KRT8 expression and stalled AT2-to-AT1 differentiation, with TGFβ1 effects being partially IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived Krt8+ transitional cells and deletion of Il11ra1 in AT2 lineage cells prevented the accumulation of Krt8+ transitional cells, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11 antibodies. scRNA-seq analysis of lung epithelial cells from mice with deletion of Il11ra1 in AT2 lineage cells further identified the importance of IL11 signaling for the potentiation and polarization of a disease-causing, ECM producing KRT8+ transitional cells that contributes to pathological lung remodeling. Overall, our data show that IL11 maintains damaged AT2 cells in a transitional state, impairs reparative AT1 differentiation and impairs endogenous alveolar regeneration to cause fibrotic lung disease.

2024-08-12 | GSE261793 | GEO

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

Project description:Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

| PRJNA1089084 | ENA

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration [RNA-seq]

Project description:Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration [RNA-seq]

| PRJNA903473 | ENA

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration [scRNA-Seq]

Project description:Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration [scRNA-Seq]

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Telomere dysfunction causes alveolar stem cell failure.

Project description:Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.

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Stat3-Bdnf-TrkB axis promotes alveolar regeneration

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-06-01 | GSE132535 | GEO

Characterization of Interleukin 11-producing fibroblasts that constitute a niche for tumor development

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-02-22 | GSE141644 | GEO

Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-07-11 | GSE207930 | GEO

Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.

Project description:Telomeres are short in type II alveolar epithelial cells (AECs) of patients with idiopathic pulmonary fibrosis (IPF). Whether dysfunctional telomeres contribute directly to development of lung fibrosis remains unknown. The objective of this study was to investigate whether telomere dysfunction in type II AECs, mediated by deletion of the telomere shelterin protein TRF1, leads to pulmonary fibrosis in mice (SPC-Cre TRF1fl/fl mice). Deletion of TRF1 in type II AECs for 2 weeks increased γH2AX DNA damage foci, but not histopathologic changes in the lung. Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells. Deletion of TRF1 in collagen-expressing cells caused pulmonary edema, but not fibrosis. These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis. We conclude that telomere dysfunction in type II AECs is sufficient to cause lung fibrosis, and may be a dominant molecular defect causing IPF. SPC-Cre TRF1fl/fl mice will be useful for assessing cellular and molecular mechanisms of lung fibrosis mediated by telomere dysfunction.

| S-EPMC5033906 | biostudies-literature

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