mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis
mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis
Abstract Lymphangioleiomyomatosis (LAM) is a rare disease which causes lung cysts and respiratory failure. TSC2 deficient ‘LAM cells’ with dysregulated mTOR signalling form nodules with fibroblasts causing lung injury. We examined if mTOR dysregulation could induce senescence and impair responses to lung injury. Senescence markers p21 and p16 were increased in LAM lungs and co-localised with alveolar type 2 cells. The SenMayo senescence gene panel was upregulated in LAM alveolar type 2 cells with senescence supressed by mTOR inhibition in patients. LAM cell / fibroblast spheroid cultures induced senescence markers in alveolar type 2 cell organoids, altered their growth and delayed epithelial scratch wound repair. Upstream regulator analysis predicted alveolar type 2 cell IL6 receptor activation. IL6 was produced by LAM cells, induced p16 and p21 in alveolar type 2 cells, inhibited epithelial wound resolution and was overexpressed in LAM patient serum where it was related to lung function. Wound repair in the presence of TSC2 null LAM cell / fibroblast spheroids was enhanced by the IL6 receptor antagonist Tocilizumab. Our findings show TSC2 loss induces senescence and IL6 production which are associated with impaired lung repair. Targeting IL6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.
Lim Kyungtae、Xu Yan、Chen Ken、Miller Suzanne、Wu Yixin、Chambers Rachel、Rawlins Emma L、Babaei-Jadidi Roya、Clements Debbie、Plate Manuela、Johnson Simon R
The Wellcome Trust/Cancer Research UK Gurdon Institute and Department Physiology, Development and Neuroscience, University of Cambridge||Department of Life Sciences, Korea University, 145 Anam-Ro, Seoungbuk-Gu, Seoul 02841, South KoreaDivisions of Pulmonary Biology and Biomedical Informatics, Perinatal Institute. Cincinnati Children?ˉs Hospital Medical Center, University of Cincinnati College of MedicineNeonatology and Pulmonary Biology Perinatal Institute. Cincinnati Children?ˉs Hospital Medical CenterCentre for Respiratory Research, Translational Medical Sciences, NIHR Biomedical Research Centre and Biodiscovery Institute, School of Medicine, University of NottinghamNeonatology and Pulmonary Biology Perinatal Institute. Cincinnati Children?ˉs Hospital Medical CenterCentre for Inflammation and Tissue Repair, University College LondonThe Wellcome Trust/Cancer Research UK Gurdon Institute and Department Physiology, Development and Neuroscience, University of CambridgeCentre for Respiratory Research, Translational Medical Sciences, NIHR Biomedical Research Centre and Biodiscovery Institute, School of Medicine, University of NottinghamCentre for Respiratory Research, Translational Medical Sciences, NIHR Biomedical Research Centre and Biodiscovery Institute, School of Medicine, University of NottinghamCentre for Inflammation and Tissue Repair, University College LondonCentre for Respiratory Research, Translational Medical Sciences, NIHR Biomedical Research Centre and Biodiscovery Institute, School of Medicine, University of Nottingham
基础医学内科学分子生物学
Lim Kyungtae,Xu Yan,Chen Ken,Miller Suzanne,Wu Yixin,Chambers Rachel,Rawlins Emma L,Babaei-Jadidi Roya,Clements Debbie,Plate Manuela,Johnson Simon R.mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis[EB/OL].(2025-03-28)[2025-05-02].https://www.biorxiv.org/content/10.1101/2024.05.03.592025.点此复制
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