SHLP2 alleviates allergic asthma by inhibiting ETV5/GSDMD signaling pathway-mediated pyroptosis

Abstract

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.