FTY720 induces neutrophil extracellular traps via a NADPH oxidase-independent pathway.

Abstract

FTY720 is an immunosuppressive agent which has been approved to treat multiple sclerosis (MS). The main object of the present study is to investigate whether FTY720 has the potential to induce the formation of neutrophil extracellular traps (NETs) in vitro. Using Sytox Green assay and fluorescence microscopy, our results showed that FTY720 trigged the NET formation. In contrast to classic NET formation induced by Phorbol 12-myristate 13-acetate (PMA), FTY720-induced NETs were detected earlier and independent of NADPH oxidase (NOX) activity. Pharmacological inhibitor experiments indicated that autophagy was also required for the NET formation induced by FTY720. Moreover, p38 and AKT inhibitor significantly suppressed the NET formation by FTY720, whereas ERK inhibitor had no effect, suggesting that FTY720-induced NETs depended on the activation of p38 and AKT. We further found that citrullination of histone H3 and peptidylarginine deiminase 4 (PAD4) did not mediated FTY720-induced NET formation. Interestingly, necroptosis signaling activation was involved in the vital NET formation by FTY720, however, plasma membrane rupture resulting from necroptosis was not a major component of NET formation described here. Collectively, these findings indicated that FTY720 could be a potential antibacterial drug to protect host against pathogen infection.

• Authors: Lanqiu Zhang, Hejun Gao, Lei Yang, Tianyu Liu, Qi Zhang, Jing Xun, Caixia Li, Lihua Cui, Ximo Wang
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 711 Pg. 109015 (10 30 2021) ISSN: 1096-0384 [Electronic] United States
• PMID: 34437865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Immunosuppressive Agents
• Proto-Oncogene Proteins c-akt
• p38 Mitogen-Activated Protein Kinases
• Fingolimod Hydrochloride

Topics

• Autophagy (physiology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Extracellular Traps (drug effects)
• Fingolimod Hydrochloride (pharmacology)
• Humans
• Immunosuppressive Agents (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Necroptosis (drug effects)
• Neutrophils (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)