Eotaxin-1/CCL11 promotes cellular senescence in human-derived fibroblasts through pro-oxidant and pro-inflammatory pathways

Frontiers in Immunology

Immunology

Rafael Moura Maurmann¹  Florencia María Barbé-Tuana²  Fatima T. C. R. Guma³  Patrícia Lavandoski³  Vinícius Pierdoná³  Lucas Kich Grun⁴ 

[1]Programa de Pós-Graduação em Biologia Celular e Molecular da Escola de Ciências da Saúde e da Vida - Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

[2]Programa de Pós-Graduação em Biologia Celular e Molecular da Escola de Ciências da Saúde e da Vida - Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

[3]Programa de Pós-Graduação em Pediatria e Saúde de Criança da Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

[4]Programa de Pós-Graduação em Ciências Biológicas, Bioquímica do Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde da Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

[5]Programa de Pós-Graduação em Pediatria e Saúde de Criança da Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

关键词: CCL11;    eotaxin-1;    senescence;    fibroblasts;    asthma;    premature aging;    lung;   

DOI  :  10.3389/fimmu.2023.1243537

 received in 2023-06-20, accepted in 2023-09-18,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionEotaxin-1/CCL11 is a pivotal chemokine crucial for eosinophil homing to the lungs of asthmatic patients. Recent studies also suggest that CCL11 is involved in the aging process, as it is upregulated in elderly, and correlated with shorter telomere length in leukocytes from asthmatic children. Despite its potential pro-aging effects, the precise contribution of CCL11 and the underlying mechanisms involved in the promotion of cellular senescence remains unclear. Therefore, the primary goal of this study was to explore the role of CCL11 on senescence development and the signaling pathways activated by this chemokine in lung fibroblasts.MethodsTo investigate the targets potentially modulated by CCL11, we performed an in silico analysis using PseudoCell. We validated in vitro the activation of these targets in the human lung fibroblast cell line MRC-5 following rhCCL11 exposure. Finally, we performed differential gene expression analysis in human airway epithelial cells of asthmatic patients to assess CCL11 signaling and activation of additional senescent markers.ResultsOur study revealed that eotaxin-1/CCL11 promote reactive oxygen secretion (ROS) production in lung fibroblasts, accompanied by increased activation of the DNA damage response (DDR) and p-TP53 and γH2AX. These modifications were accompanied by cellular senescence promotion and increased secretion of senescence-associated secretory phenotype inflammatory cytokines IL-6 and IL-8. Furthermore, our data show that airway epithelial lung cells from atopic asthmatic patients overexpress CCL11 along with aging markers such as CDKN2A (p16INK4a) and SERPINE1.DiscussionThese findings provide new insights into the mechanisms underlying the pro-aging effects of CCL11 in the lungs of asthmatic patients. Understanding the role of CCL11 on senescence development may have important implications for the treatment of age-related lung diseases, such as asthma.

【 授权许可】

Unknown   
Copyright © 2023 Lavandoski, Pierdoná, Maurmann, Grun, Guma and Barbé-Tuana