Secreted phospholipase A2 XIIA triggers a mitochondrial damage-induced senescence in chronic obstructive pulmonary disease fibroblasts

• Published in: Free radical biology & medicine Vol. 205; pp. 129 - 140
• Main Authors: Herath, Danushki, Even, Benjamin, Oranger, Mathilde, Foresti, Roberta, Papy, Dulce, Boyer, Laurent, Boczkowski, Jorge, Dagouassat, Maylis
• Format: Journal Article
• Language: English
• Published: Elsevier 29.05.2023
• Subjects: Life Sciences; Senescence; Aging; Fibroblasts; Emphysema; Secreted phospholipase; COPD
• ISSN: 0891-5849
• DOI: 10.1016/j.freeradbiomed.2023.05.025

Lung fibroblast senescence is involved in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the mechanisms underlining this phenomenon are still poorly understood. Secreted phospholipases (sPLA2, a subclass of phospholipases) are secreted by senescent cells and can in turn induce senescence. However, their role in fibroblasts senescence in COPD is unknown. Objectives: The aim of this study was to analyze the role of sPLA2 in pulmonary fibroblast senescence. Methods: Fibroblasts were isolated from patients with COPD and control subjects, and senescence markers and inflammatory profile was analyzed. sPLA2 levels were quantified in serum of COPD and controls. Main results: In comparison with non-smokers and smoker controls, senescent lung COPD fibroblasts exhibited a higher mRNA and protein expression of the sPLA2 isoform XIIA and of syndecan 4 (one of its receptors). sPLA2 XIIA induced in turn senescence of non-senescent pulmonary fibroblasts via a pathway involving consecutively syndecan 4, activation of MAPK and p-serine 727 STAT-3, increased mitochondrial ROS production, and activation of AMPK/p53. This pathway was associated with a specific inflammatory secretome (IL-10, IL-12 and TNFα), globally suggesting occurrence of a mitochondrial damage-induced senescence. COPD fibroblasts were more susceptible to this sPLA2 XIIA effect than cells from controls subjects. sPLA2 XIIA levels were significantly higher in serum from COPD patients as compared to controls. Conclusion: sPLA2 XIIA is involved in senescence in COPD and could be a potential target to dampen this process.