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Journal Articles European Respiratory Journal Year : 2021

Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease

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David Bernard

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.
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Dates and versions

inserm-03420591 , version 1 (09-11-2021)

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Delphine Beaulieu, Aya Attwe, Marielle Breau, Larissa Lipskaia, Elisabeth Marcos, et al.. Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease. European Respiratory Journal, 2021, 58 (2), pp.2000752. ⟨10.1183/13993003.00752-2020⟩. ⟨inserm-03420591⟩
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