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In Vivo Assessment of Alveolar Macrophage Efferocytosis Following Ozone Exposure
Published on: October 22, 2019
Macrophage migration inhibitory factor exacerbates asthmatic airway remodeling via dynamin-related protein 1-mediated
Jin Liu1, Yuqian Chen1, Huan Chen1
1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China.
Background:
Macrophage 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.
Methods:
In 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.
Results:
In 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.
Conclusions:
The 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.
Insights
Macrophage migration inhibitory factor (MIF) promotes asthma by activating autophagy and degrading E-cadherin via the ERK/Drp1 pathway. Targeting this pathway may offer new asthma treatments.
Area of Science:
- Cell Biology
- Immunology
- Respiratory Medicine
Background:
- Macrophage migration inhibitory factor (MIF) and aberrant mitochondrial fission are implicated in asthma pathogenesis.
- The precise role of Drp1-mediated mitochondrial fission in MIF-induced airway smooth muscle cell proliferation and airway remodeling remains unclear.
Purpose of the Study:
- To elucidate the role of Drp1-mediated mitochondrial fission and its downstream targets in MIF-induced airway smooth muscle cell proliferation and chronic asthma airway remodeling.
Main Methods:
- Primary cultured airway smooth muscle cells (ASMCs) and ovalbumin (OVA)-induced asthmatic rat models were used.
- Assays included CCK-8, EdU, Western blotting, transmission electron microscopy, and histological staining.
- Evaluated were cell proliferation, signaling pathways (ERK1/2, Drp1), autophagy, E-cadherin expression, and asthma development markers.
Main Results:
- MIF activated ERK1/2, leading to Drp1 phosphorylation, enhanced autophagy, and reduced E-cadherin, promoting ASMC proliferation.
- In asthmatic rats, MIF inhibition, mitochondrial fission suppression, or autophagy inhibition attenuated airway remodeling.
Conclusions:
- MIF promotes asthma airway remodeling by activating autophagy and E-cadherin degradation through the ERK/Drp1 signaling pathway.
- Targeting the MIF/ERK/Drp1 pathway presents potential therapeutic strategies for asthma prevention and treatment.
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