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

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 and Simon R. Johnson ()
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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
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
Yan Xu: University of Cincinnati College of Medicine
Simon R. Johnson: University of Nottingham

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64036-3

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