Apoptosis de células T más susceptible al complejo MPO/NE de NETs liberadas por neutrófilos sobreactivados

Sepsis, characterized by infection-induced systemic inflammatory response, involves polymorphonuclear leukocytes (PMNs or Neutrophils)-T cell dysregulation. However, the precise mechanisms of PMN-driven T cell apoptosis via neutrophil extracellular traps (NETs) and their protease cargo (myeloperoxidase [MPO], neutrophil elastase [NE]), along with potential mitochondrial transfer-mediated protection, remain unclear. Using PMA-activated PMNs in coculture systems, we assessed NETs formation, T cell apoptosis/proliferation/exhaustion, DNA damage, and mitochondrial function through flow cytometry, electron microscopy, immunofluorescence, and molecular assays, with validation in LPS-challenged mice. Key findings:1) Phorbol 12-myristate 13-acetate(PMA)-activated PMNs released NETs-MPO/NE complexes that directly trapped T cells, inducing apoptosis.2) Nuclear-translocated MPO/NE triggered DNA double-strand breaks and mitochondrial membrane permeabilization, activating intrinsic apoptosis.3) MPO/NE inhibitors or NETs degradation by DNase I significantly reduced apoptosis.4) Mitochondrial transfer from resting PMNs partially restored T cell bioenergetics and attenuated apoptosis. Conclusion: NETs-derived MPO/NE promote T cell apoptosis via nuclear DNA damage and mitochondrial dysfunction, while NETs clearance, protease inhibition, or mitochondrial transfer offer therapeutic potential.