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SHLP2 alleviates allergic asthma by inhibiting ETV5/GSDMD signaling pathway-mediated pyroptosis
Wenlong Zhang1, Yan Wang2, Chenhui Ma2
1Department of Respiratory and Critical Care Medicine, Jiangnan University Medical Center, 68 Zhongshan Road, Wuxi 2140002, Jiangsu Province, PR China; Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, Jiangsu Province, PR China.
Background:
Allergic asthma (AA) is a lung disease characterized by impaired respiratory function and significant infiltration of inflammatory cells. Human Protein-Mimicking Peptide-2 (SHLP2) is a recently discovered mitochondria-encoded peptide that plays a crucial role in mitochondrial retrograde signaling pathways. However, its potential utility in mitigating AA remains unexplored. Our study investigates the therapeutic potential of SHLP2 in AA.
Results:
We found that SHLP2 expression was significantly lower in the serum of patients with AA and correlated with key AA biomarkers. Exogenous SHLP2 supplementation alleviated house dust mites (HDM)-induced lung inflammation and airway barrier damage in mice. Additionally, SHLP2 ameliorated mitochondrial damage and inhibited pyroptosis in bronchial epithelial cells. At the mechanistic level, we identified a binding site between SHLP2 and the promoter region of the ETS Variant Transcription Factor 5 (ETV5) using a luciferase reporter assay. SHLP2 inhibited the transcription of downstream GSDMD, thereby suppressing pyroptosis.
Conclusions:
Overexpression of ETV5 improved mitochondrial function and reduced pyroptosis in bronchial epithelial cells. However, exogenous SHLP2 supplementation failed to reverse the exacerbation of HDM-induced lung inflammation and airway barrier damage caused by ETV5 knockout in mice. These findings highlight SHLP2 as a key ETV5/GSDMD signaling pathway regulator, inhibiting pyroptosis and mitigating AA progression.
Insights
Human Protein-Mimicking Peptide-2 (SHLP2) may treat allergic asthma (AA). Lower SHLP2 levels correlate with AA, and SHLP2 supplementation reduced lung inflammation and cell damage in mice by regulating the ETV5/GSDMD pathway.
Area of Science:
- Mitochondrial biology
- Immunology
- Respiratory medicine
Background:
- Allergic asthma (AA) is a chronic respiratory disease marked by inflammation and impaired lung function.
- Mitochondria-encoded Human Protein-Mimicking Peptide-2 (SHLP2) is involved in mitochondrial retrograde signaling.
- The therapeutic potential of SHLP2 in AA has not been previously investigated.
Purpose of the Study:
- To investigate the therapeutic potential of SHLP2 in allergic asthma.
- To explore the role of SHLP2 in regulating inflammation and cell damage in AA.
Main Methods:
- Serum analysis of SHLP2 levels in AA patients.
- In vivo studies using house dust mite (HDM)-induced AA mouse models.
- In vitro studies on bronchial epithelial cells to assess mitochondrial function and pyroptosis.
- Luciferase reporter assays to identify molecular interactions between SHLP2 and ETV5.
Main Results:
- SHLP2 expression was significantly reduced in AA patients' serum and correlated with AA biomarkers.
- Exogenous SHLP2 administration alleviated HDM-induced lung inflammation and airway barrier damage in mice.
- SHLP2 improved mitochondrial function and inhibited pyroptosis in bronchial epithelial cells by targeting the ETV5 promoter and suppressing GSDMD transcription.
Conclusions:
- SHLP2 acts as a regulator of the ETV5/GSDMD signaling pathway.
- SHLP2 inhibits pyroptosis and mitigates the progression of allergic asthma.
- Targeting the SHLP2 pathway offers a potential therapeutic strategy for AA.
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