IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells

Widjaja, Anissa A.; Sivakumar, V.; Goh, Joyce Wei Ting; Tan, Jessie; Shekeran, Shamini Guna; Carling, David; Lim, Wei‐Wen; Cook, Stuart A.

doi:10.1016/j.isci.2022.104806

Cited by 26 publications

(22 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). These data reinforce the importance of IL11 for TGFβ effects 15 and the activation of mTORC1 by IL11 18,26 while suggesting a role for IL11 in TEC mesenchymal transition and inflammation.…”

Section: Il11 Induces Pro-inflammatory and Mesenchymal Genes In Tubul...supporting

confidence: 74%

“…IL11 causes short-term STAT3 and sustained ERK activation across multiple cell types 18,[24][25][26] . We assessed IL11-stimulated STAT3 and ERK activation in TECs and determined if this was linked with mesenchymal transition.…”

Section: Autocrine Il11 Activity Causes Tubular Epithelial Cell Mesen...mentioning

confidence: 99%

“…We recently identified interleukin 11 (IL11) as a pro-fibrotic factor in fibroblasts and showed that IL11 contributes to renal fibrosis in a mouse model of AKI 15 and renal failure in genetically-driven glomerular disease 16 . IL11 can also stimulate epithelial cell EMT 17,18 and in epithelial cancer cells, TGFβ1 specifically upregulates SNAI1, HAS2, and IL11 19 .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3β inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFβ reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney.

show abstract

Section: Il11 Induces Pro-inflammatory and Mesenchymal Genes In Tubul...supporting

confidence: 74%

Section: Autocrine Il11 Activity Causes Tubular Epithelial Cell Mesen...mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Next, we showed that IL-11 negatively affected organoid formation. The effect of IL-11 on lung epithelial cells has been of limited research focus, though it was recently shown that both A549 cells and H1792 cells are able to respond to IL-11 by activating downstream ERK signaling [42]. Additionally, IL-11 has been studied in human embryonic stem cell (hESC) derived organoids that model Hermansky-Pudlak syndrome associated interstitial pneumonia (HPSIP), which also recapitulate features of IPF.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IL-11 disrupts alveolar epithelial progenitor function

Kortekaas

Borghuis

et al. 2022

Preprint

View full text Add to dashboard Cite

IL11 is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung. The alveolar architecture is disrupted in IPF, yet the effect of IL11 on dysregulated alveolar repair associated with IPF remains to be elucidated. We hypothesized that epithelial-fibroblast communication associated with lung repair is disrupted by IL11. Thus, we studied whether IL11 affects the repair responses of alveolar lung epithelium using mouse lung organoids and precision cut lung slices (PCLS). Additionally, we assessed the anatomical distribution of IL11 and IL11 receptor in human control and IPF lungs using immunohistochemistry. IL11 protein was observed in human control lungs in airway epithelium, macrophages and in IPF lungs, in areas of AT2 cell hyperplasia. IL11R staining was predominantly present in smooth muscle and macrophages. In mouse organoid cocultures of epithelial cells with lung fibroblasts, IL11 decreased organoid number and reduced the fraction of pro-SPC expressing organoids, indicating dysfunctional regeneration initiated by epithelial progenitors. In mouse PCLS alveolar marker gene expression declined, whereas airway markers were increased. The response of primary human fibroblasts to IL11 on gene expression level was minimal, though bulk RNAsequencing revealed IL11 modulated a number of processes which may play a role in IPF, including unfolded protein response, glycolysis and Notch signaling. In conclusion, IL11 disrupts alveolar epithelial regeneration by inhibiting progenitor activation and suppressing the formation of mature alveolar epithelial cells. The contribution of dysregulated fibroblast epithelial communication to this process appears to be limited.

show abstract

Emerging therapeutic targets in systemic sclerosis

O’Reilly

2024

J Mol Med

View full text Add to dashboard Cite

IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells

Cited by 26 publications

References 55 publications

Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease

Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease

IL-11 disrupts alveolar epithelial progenitor function

Emerging therapeutic targets in systemic sclerosis

Contact Info

Product

Resources

About