Delphine Beaulieu1,2, Aya Attwe1,3,2, Marielle Breau1, Larissa Lipskaia1, Elisabeth Marcos1, Emmanuelle Born1, Jin Huang1, Shariq Abid1, Geneviève Derumeaux1, Amal Houssaini1, Bernard Maitre1, Marine Lefevre4, Nora Vienney1, Philippe Bertolino5, Sara Jaber5, Hiba Noureddine3, Delphine Goehrig5, David Vindrieux5, David Bernard5,6, Serge Adnot7,8,6. 1. INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France. 2. These two authors contributed equally. 3. Environmental Health Research Laboratory (EHRL), Faculty of Sciences V, Lebanese University, Nabatieh, Lebanon. 4. Département Anatomopathologie, Institut Mutualiste Montsouris, Paris, France. 5. Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052/CNRS 5286, Université de Lyon, Centre Léon Bérard, Lyon, France. 6. These two authors are joint senior authors. 7. INSERM U955, Département de Physiologie-Explorations Fonctionnelles and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France serge.adnot@inserm.fr. 8. Institute for Lung Health, University of Giessen, Giessen, Germany.
Abstract
BACKGROUND: Cell senescence is a key process in age-associated dysfunction and diseases, notably chronic obstructive pulmonary disease (COPD). We previously identified phospholipase A2 receptor 1 (PLA2R1) as a positive regulator of cell senescence acting via Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Its role in pathology, however, remains unknown. Here, we assessed PLA2R1-induced senescence in COPD and lung emphysema pathogenesis. METHODS: We assessed cell senescence in lungs and cultured lung cells from patients with COPD and controls subjected to PLA2R1 knockdown, PLA2R1 gene transduction and treatment with the JAK1/2 inhibitor ruxolitinib. To assess whether PLA2R1 upregulation caused lung lesions, we developed transgenic mice overexpressing PLA2R1 (PLA2R1-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying the Pla2r1 gene (LV-PLA2R1 mice). RESULTS: We found that PLA2R1 was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs. PLA2R1 knockdown extended the population doubling capacity of these cells and inhibited their pro-inflammatory senescence-associated secretory phenotype (SASP). PLA2R1-mediated cell senescence in COPD was largely reversed by treatment with the potent JAK1/2 inhibitor ruxolitinib. Five-month-old PLA2R1-TG mice exhibited lung cell senescence, and developed lung emphysema and lung fibrosis together with pulmonary hypertension. Treatment with ruxolitinib induced reversal of lung emphysema and fibrosis. LV-PLA2R1-treated mice developed lung emphysema within 4 weeks and this was markedly attenuated by concomitant ruxolitinib treatment. CONCLUSIONS: Our data support a major role for PLA2R1 activation in driving lung cell senescence and lung alterations in COPD. Targeting JAK1/2 may represent a promising therapeutic approach for COPD.
BACKGROUND: Cell senescence is a key process in age-associated dysfunction and diseases, notably chronic obstructive pulmonary disease (COPD). We previously identified phospholipase A2 receptor 1 (PLA2R1) as a positive regulator of cell senescence acting via Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Its role in pathology, however, remains unknown. Here, we assessed PLA2R1-induced senescence in COPD and lung emphysema pathogenesis. METHODS: We assessed cell senescence in lungs and cultured lung cells from patients with COPD and controls subjected to PLA2R1 knockdown, PLA2R1 gene transduction and treatment with the JAK1/2 inhibitor ruxolitinib. To assess whether PLA2R1 upregulation caused lung lesions, we developed transgenic mice overexpressing PLA2R1 (PLA2R1-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying the Pla2r1 gene (LV-PLA2R1 mice). RESULTS: We found that PLA2R1 was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs. PLA2R1 knockdown extended the population doubling capacity of these cells and inhibited their pro-inflammatory senescence-associated secretory phenotype (SASP). PLA2R1-mediated cell senescence in COPD was largely reversed by treatment with the potent JAK1/2 inhibitor ruxolitinib. Five-month-old PLA2R1-TG mice exhibited lung cell senescence, and developed lung emphysema and lung fibrosis together with pulmonary hypertension. Treatment with ruxolitinib induced reversal of lung emphysema and fibrosis. LV-PLA2R1-treated mice developed lung emphysema within 4 weeks and this was markedly attenuated by concomitant ruxolitinib treatment. CONCLUSIONS: Our data support a major role for PLA2R1 activation in driving lung cell senescence and lung alterations in COPD. Targeting JAK1/2 may represent a promising therapeutic approach for COPD.
Authors: Miranda K Culley; Jingsi Zhao; Yi Yin Tai; Ying Tang; Dror Perk; Vinny Negi; Qiujun Yu; Chen-Shan C Woodcock; Adam Handen; Gil Speyer; Seungchan Kim; Yen-Chun Lai; Taijyu Satoh; Annie Mm Watson; Yassmin Al Aaraj; John Sembrat; Mauricio Rojas; Dmitry Goncharov; Elena A Goncharova; Omar F Khan; Daniel G Anderson; James E Dahlman; Aditi U Gurkar; Robert Lafyatis; Ahmed U Fayyaz; Margaret M Redfield; Mark T Gladwin; Marlene Rabinovitch; Mingxia Gu; Thomas Bertero; Stephen Y Chan Journal: J Clin Invest Date: 2021-06-01 Impact factor: 14.808