Macrophage migration inhibitory factor exacerbates asthmatic airway remodeling via dynamin-related protein 1-mediated autophagy activation

Respiratory Research

Research

Danyang Li¹  Yuanjie Qiu¹  Jian Wang¹  Nirui Shen¹  Jin Liu¹  Huan Chen¹  Yuqian Chen¹  Jia Zhang¹  Limin Chai¹  Qingting Wang¹  Yan Wang¹  Manxiang Li¹  Qianqian Zhang¹ 

[1] Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277, West Yanta Road, 710061, Xi’an, Shaanxi, People’s Republic of China;

关键词: Asthma;    Macrophage migration inhibitory factor;    GTPase dynamin-related protein 1;    Autophagy;    Airway remodeling;   

DOI  :  10.1186/s12931-023-02526-y

 received in 2023-06-07, accepted in 2023-08-31,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMacrophage migration inhibitory factor (MIF) and GTPase dynamin-related protein 1 (Drp1)-dependent aberrant mitochondrial fission are closely linked to the pathogenesis of asthma. However, it is unclear whether Drp1-mediated mitochondrial fission and its downstream targets mediate MIF-induced proliferation of airway smooth muscle cells (ASMCs) in vitro and airway remodeling in chronic asthma models. The present study aims to clarify these issues.MethodsIn this study, primary cultured ASMCs and ovalbumin (OVA)-induced asthmatic rats were applied. Cell proliferation was detected by CCK-8 and EdU assays. Western blotting was used to detect extracellular signal-regulated kinase (ERK) 1/2, Drp1, autophagy-related markers and E-cadherin protein phosphorylation and expression. Inflammatory cytokines production, airway reactivity test, histological staining and immunohistochemical staining were conducted to evaluate the development of asthma. Transmission electron microscopy was used to observe the mitochondrial ultrastructure.ResultsIn primary cultured ASMCs, MIF increased the phosphorylation level of Drp1 at the Ser616 site through activation of the ERK1/2 signaling pathway, which further activated autophagy and reduced E-cadherin expression, ultimately leading to ASMCs proliferation. In OVA-induced asthmatic rats, MIF inhibitor 4-iodo-6-phenylpyrimidine (4-IPP) treatment, suppression of mitochondrial fission by Mdivi-1 or inhibiting autophagy with chloroquine phosphate (CQ) all attenuated the development of airway remodeling.ConclusionsThe present study provides novel insights that MIF promotes airway remodeling in asthma by activating autophagy and degradation of E-cadherin via ERK/Drp1 signaling pathway, suggesting that targeting MIF/ERK/Drp1 might have potential therapeutic value for the prevention and treatment of asthma.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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