mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease of women in which TSC2 deficient 'LAM cells' with dysregulated mTOR signalling and recruited fibroblasts form nodules causing lung cysts and respiratory failure. We examine if mTOR dysregulation can induce senescence and impair the response to lung injury in LAM. The senescence markers p21, p16 and the SenMayo gene set are increased in LAM lungs and colocalise with alveolar type 2 cells. LAM models induce mTOR dependent senescence in alveolar type 2 cell organoids in vitro and in vivo. IL-6 produced by LAM cells, induces p16 and p21 in alveolar type 2 cells, inhibits epithelial wound resolution and is related to lung function in LAM patients. Rapamycin and the IL-6 receptor antagonist Tocilizumab reduce alveolar type 2 cell organoid p21 accumulation and Tocilizumab enhances epithelial wound repair. Targeting IL-6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.

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Publication Details

Journal
Nature Communications
Published
2025-10-09
DOI
https://doi.org/10.1038/s41467-025-64036-3
Citations
2
Primary Topic
Tuberous Sclerosis Complex Research
Type
article
Field-Weighted Citation Impact
2.33

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article

mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

Ryan W. Rue, Yan Xu, Simon R. Johnson, Vera P. Krymskaya et al.
2 citations
Nature Communications
Tuberous Sclerosis Complex Research
2.33
article

mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

Ryan W. Rue, Yan Xu, Simon R. Johnson, Vera P. Krymskaya, Yixin Wu, Emma L. Rawlins, Debbie Clements, Roya Babaei‐Jadidi, Manuela Platé, Kyungtae Lim, Rachel C. Chambers, S. Miller, Ken Chen
article en
2 citations

Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease of women in which TSC2 deficient 'LAM cells' with dysregulated mTOR signalling and recruited fibroblasts form nodules causing lung cysts and respiratory failure. We examine if mTOR dysregulation can induce senescence and impair the response to lung injury in LAM. The senescence markers p21, p16 and the SenMayo gene set are increased in LAM lungs and colocalise with alveolar type 2 cells. LAM models induce mTOR dependent senescence in alveolar type 2 cell organoids in vitro and in vivo. IL-6 produced by LAM cells, induces p16 and p21 in alveolar type 2 cells, inhibits epithelial wound resolution and is related to lung function in LAM patients. Rapamycin and the IL-6 receptor antagonist Tocilizumab reduce alveolar type 2 cell organoid p21 accumulation and Tocilizumab enhances epithelial wound repair. Targeting IL-6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.

Nature CommunicationsVol. 16(1)
Cincinnati Children's Hospital Medical Center (US), University of Nottingham (GB), Korea University (KR), University of Cambridge (GB), The Gurdon Institute (GB), Perinatal Institute (GB), Nottingham Biomedical Research Centre (GB), Centre for Inflammation Research (GB), University College London (GB), University of Pennsylvania (US), Wellcome Trust (GB)
Fundació la Marató de TV3, National Institute for Health and Care Research, Medical Research Council, National Heart, Lung, and Blood Institute
Openalex Percentile: Top 10%
Tuberous Sclerosis Complex Research
2.33
DOIOpen Access PDFOpenAlex
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