Mechanistic Study of SRSF1-Mediated Inhibition of Treg Cell Function via the mTORC1/ULK1 Signalling Axis Through Mitophagy in Asthma

Abstract

Objective

This study examines the role of serine/arginine-rich splicing factor 1 (SRSF1) in airway inflammation in asthma and the molecular mechanisms in mitophagy and metabolic homeostasis in regulatory T cells (Tregs).

Methods

Bronchoalveolar lavage fluid (BALF) was collected from asthma patients and healthy controls to assess SRSF1 expression and autophagy, and to analyse the correlation of SRSF1 with Treg cell functional markers and lung function. The ovalbumin (OVA)-induced asthma mouse model was established, with the OVA, OVA+shSRSF1, OVA+rapamycin, and OVA+shSRSF1+MHY1485 groups established. Additionally, an OVA+PM2.5 group was set up. Treg cells were isolated from lung tissue to evaluate Treg cell mitophagy, glucose metabolism reprogramming, mitochondrial function, and immunosuppressive activity.

Results

SRSF1 levels in BALF cells from asthma patients were notably elevated and showed negative correlations with FOXP3 expression in Treg cells and FEV₁% pred. In OVA-induced asthmatic mice, SRSF1 was upregulated in Treg cells, accompanied by increased phosphorylation of mTOR and ULK1 at Ser757, leading to defects in mitophagy and metabolic reprogramming. Silencing SRSF1 or rapamycin treatment reversed the aforementioned autophagy inhibition and metabolic dysregulation, restored Treg cell numbers and suppressive function, and alleviated airway inflammation and airway hyperresponsiveness. In contrast, the mTORC1 activator MHY1485 counteracted the protective effects of shSRSF1. PM2.5 exposure further exacerbated these changes, which were dependent on SRSF1 expression.

Conclusion

SRSF1 modulates the mTORC1/ULK1 axis and is associated with impaired Treg mitophagy and metabolic reprogramming in asthma. Targeting SRSF1 or mTORC1 may represent a promising therapeutic strategy for the prevention and treatment of asthma.