T-cell apoptosis is more susceptible to overactivated neutrophils delivered-NETs-MPO/NE complex

Area of Science:

• Immunology
• Cell Biology
• Pathophysiology

Background:

• Sepsis involves immune cell dysregulation, particularly between polymorphonuclear leukocytes (PMNs) and T cells.
• Neutrophil extracellular traps (NETs) and their enzymes are implicated in sepsis pathogenesis, but mechanisms of T cell apoptosis are unclear.

Purpose of the Study:

• To elucidate the mechanisms by which NETs-derived proteases (MPO, NE) induce T cell apoptosis.
• To investigate the role of mitochondrial transfer in protecting T cells from NET-induced apoptosis.

Main Methods:

• Coculture of Phorbol 12-myristate 13-acetate (PMA)-activated PMNs with T cells.
• Assessment of NETs formation, T cell apoptosis, proliferation, exhaustion, DNA damage, and mitochondrial function.
• Flow cytometry, electron microscopy, immunofluorescence, molecular assays, and in vivo validation in LPS-challenged mice.

Main Results:

• PMA-activated PMNs released NETs-MPO/NE complexes that induced T cell apoptosis.
• Nuclear-translocated MPO/NE caused DNA double-strand breaks and mitochondrial dysfunction, activating intrinsic apoptosis.
• NETs degradation (DNase I) or protease inhibition reduced T cell apoptosis.
• Mitochondrial transfer from resting PMNs partially restored T cell function and reduced apoptosis.

Conclusions:

• NETs-derived MPO/NE drive T cell apoptosis through DNA damage and mitochondrial dysfunction.
• NETs clearance, protease inhibition, and mitochondrial transfer represent potential therapeutic strategies for sepsis-induced T cell apoptosis.