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Dusquetide Regulates SQSTM1/p62-Mediated Mitophagy to Alleviate PM2.5-Aggravated Airway Inflammation in Asthma
Jie Gao1,2, Ji-Liu Liu1,2, Man-Ling Jiang1,2
1Allergy and Precision Medicine Laboratory, Department of Respiratory and Critical Care Medicine,The Third People's Hospital of Chengdu,College of Medicine,Southwest Jiaotong University, Chengdu 610031, China.
Abstract:
Objective To investigate the pathological mechanism by which fine particulate matter (PM2.5) exacerbates asthma,with a focus on SQSTM1/p62-mediated mitophagy,and to evaluate the regulatory and therapeutic potential of dusquetide in this process. Methods A house dust mite (HDM)-induced asthma model was established with 6- to 8-week-old female C57BL/6 mice,which were then exposed to PM2.5.Control,HDM,HDM+PM2.5 (HP),and intervention (HP+Mdivi-1 and HP+dusquetide) groups were established.Airway hyperresponsiveness was assessed through whole-body plethysmography,and airway inflammation and mucus secretion were evaluated by HE and PAS staining.Immunofluorescence assay was employed to detect the co-localization of TOMM20 and LC3B.Key factors were screened and validated by LC-MS/MS-based mitochondrial proteomics. Results PM2.5 exposure enhanced airway hyperresponsiveness (P<0.01),exacerbated inflammation and mucus secretion (P<0.01),and increased TOMM20 and LC3B co-localization signals (P<0.01) in HDM-sensitized mice.Mdivi-1 inhibition of mitophagy reduced inflammation (P<0.01).Mitochondrial proteomics identified SQSTM1/p62 as a core regulatory factor,whose expression was up-regulated after PM2.5 exposure (P<0.01).Dusquetide intervention inhibited SQSTM1/p62 function and mitophagy (P<0.01),reduced airway hyperresponsiveness in mice of the HP group (P<0.01),and alleviated inflammatory manifestations (P<0.01). Conclusion PM2.5 exacerbates HDM-induced asthma pathology by activating SQSTM1/p62-mediated mitophagy,while dusquetide effectively alleviates this process,demonstrating the potential as a therapeutic target for PM2.5-related asthma.
Insights
Fine particulate matter (PM2.5) worsens asthma by activating SQSTM1/p62-mediated mitophagy. Dusquetide treatment alleviates this PM2.5-induced asthma exacerbation, indicating its therapeutic potential.
Area of Science:
- Environmental Health
- Pulmonology
- Cellular Biology
Background:
- Asthma is a chronic respiratory disease exacerbated by fine particulate matter (PM2.5).
- The precise pathological mechanisms linking PM2.5 exposure to asthma exacerbation require further elucidation.
- Mitophagy, a selective form of autophagy, plays a role in cellular quality control and has been implicated in inflammatory diseases.
Purpose of the Study:
- To investigate the role of SQSTM1/p62-mediated mitophagy in PM2.5-induced asthma exacerbation.
- To evaluate dusquetide as a potential therapeutic agent for PM2.5-related asthma.
Main Methods:
- A house dust mite (HDM)-induced asthma mouse model was utilized.
- Mice were exposed to PM2.5, and various groups received interventions including Mdivi-1 and dusquetide.
- Airway hyperresponsiveness, inflammation, mucus secretion, and mitophagy markers (TOMM20, LC3B, SQSTM1/p62) were assessed using plethysmography, histological staining, immunofluorescence, and mitochondrial proteomics.
Main Results:
- PM2.5 exposure significantly increased airway hyperresponsiveness, inflammation, and mucus secretion in HDM-sensitized mice.
- PM2.5 exposure upregulated SQSTM1/p62 expression and enhanced mitophagy, indicated by increased TOMM20 and LC3B co-localization.
- Dusquetide intervention successfully inhibited SQSTM1/p62 function and mitophagy, leading to reduced airway hyperresponsiveness and inflammation.
Conclusions:
- PM2.5 exacerbates HDM-induced asthma by activating SQSTM1/p62-mediated mitophagy.
- Dusquetide demonstrates significant therapeutic potential in alleviating PM2.5-induced asthma pathology.
- Targeting SQSTM1/p62-mediated mitophagy presents a promising strategy for treating PM2.5-related asthma.
