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

Author

Listed:
  • Roya Babaei-Jadidi

    (University of Nottingham)

  • Debbie Clements

    (University of Nottingham)

  • Yixin Wu

    (Cincinnati Children’s Hospital Medical Center)

  • Ken Chen

    (Cincinnati Children’s Hospital Medical Center)

  • Suzanne Miller

    (University of Nottingham)

  • Manuela Platé

    (University College London)

  • Kyungtae Lim

    (The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge
    Korea University)

  • Ryan Rue

    (University of Pennsylvania)

  • Vera P. Krymskaya

    (University of Pennsylvania)

  • Rachel Chambers

    (University College London)

  • Emma L. Rawlins

    (The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge
    University of Cambridge)

  • Yan Xu

    (University of Cincinnati College of Medicine)

  • Simon R. Johnson

    (University of Nottingham)

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.

Suggested Citation

  • Roya Babaei-Jadidi & Debbie Clements & Yixin Wu & Ken Chen & Suzanne Miller & Manuela Platé & Kyungtae Lim & Ryan Rue & Vera P. Krymskaya & Rachel Chambers & Emma L. Rawlins & Yan Xu & Simon R. Johnso, 2025. "mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64036-3
    DOI: 10.1038/s41467-025-64036-3
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