Dasatinib Alleviates Sepsis by Restoring Regulatory T Cell Homeostasis through the SRC/ADAM10/CD25 Axis
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Sepsis-induced immune paralysis, driven by regulatory T cell (Treg) reduction, is a major cause of mortality. While A Disintegrin and Metalloproteinase 10 (ADAM10) overactivation is observed in patients with sepsis, its precise upstream regulation and role in Treg dysfunction remain unclear. Bioinformatics and clinical data from sepsis patients revealed a significant inverse correlation between ADAM10 and Treg markers. Mechanistically, SRC (Steroid receptor coactivator) kinase directly interacted with and phosphorylated ADAM10, triggering its hyperactivity. This led to excessive shedding of surface CD25 (sCD25 release), which impaired the IL-2 signaling essential for Treg differentiation. The SRC inhibitor Dasatinib dose-dependently inhibited ADAM10, restored CD25 surface expression, and rescued Treg frequency. Critically, this restorative effect was abolished by an ADAM10 agonist, confirming the specificity of the SRC-ADAM10 pathway. In septic mice, Dasatinib treatment also significantly reduced plasma sCD25, increased splenic Tregs, attenuated organ injury, and improved survival. This study elucidates a novel SRC-ADAM10-CD25 axis driving Treg reduction in sepsis and identifies Dasatinib as a potential drug repurposing candidate to restore immune homeostasis in patients with sepsis.
