Electrostatic Charge-Mediated Apoptotic Vesicle Biodistribution Attenuates Sepsis by Switching Neutrophil NETosis to Apoptosis.

Mesenchymal stem cell (MSC) therapy can attenuate organ damage and reduce mortality in sepsis; however, the detailed mechanism is not fully elucidated. In this study, it is shown that MSC-derived apoptotic vesicles (apoVs) can ameliorate multiple organ dysfunction and improve survival in septic mice. Mechanistically, it is found that tail vein-infused apoVs mainly accumulate in the bone marrow of septic mice via electrostatic charge interactions with positively charged neutrophil extracellular traps (NETs). Moreover, apoVs switch neutrophils NETosis to apoptosis via the apoV-Fas ligand (FasL)-activated Fas pathway. In summary, these findings uncover a previously unknown role of apoVs in sepsis treatment and an electrostatic charge-directed target therapeutic mechanism, suggesting that cell death is associated with disease development and therapy.

The Fas/Fas ligand apoptotic pathway is involved in abrin-induced apoptosis.

Abrin is a plant glycoprotein toxin from the seeds of Abrus precatorius, sharing similarity in structure and properties with ricin. Abrin is highly toxic, with an estimated human fatal dose of 0.1-1 µg/kg, causing death after accidental or intentional poisoning. It is a potent biological toxin warfare agent. There is no chemical antidote available against the abrin. The elucidation of molecular mechanism of abrin-induced cell death is important for development of therapy. Intrinsic pathway-mediated apoptosis has been well established in abrin-induced cell death. However, the detailed mechanism especially extrinsic receptor-mediated pathway remains uncharacterized. To assess whether some of the apoptosis known to occur after abrin exposure might be mediated by Fas/Fas ligand (Fas L) interactions, we analyzed effect of abrin on Fas pathway in Jurkat cells. Here, we report that activation of the Fas pathway is involved in abrin-induced apoptosis. Following treatment of abrin, Fas L was induced, which stimulated the Fas pathway by cross-linking Fas receptor (Fas R). Apoptosis was mediated by cleavage of the Fas R proximal caspase-8 and the downstream caspase-3, resulting in activation of the prototype caspase substrate poly-(ADP-ribose) polymerase and caspase-activated DNase. Blocking Fas L/Fas R interaction by using Fas inhibitor reduced abrin-induced apoptosis, further confirms involvement of Fas pathway. Activation of components of Fas pathway and caspases upon abrin treatment was also found in splenocytes in mice. Our findings offer new perspective for understanding the fundamental mechanism in abrin-induced apoptotic mechanism and may have implication in developing novel therapeutic strategies in the management for abrin-induced complications.