Journal
REDOX BIOLOGY
Volume 43, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2021.101983
Keywords
Neutrophil; Neutrophil extracellular traps; Amiloride; Sodium-calcium exchanger; NADPH oxidase; ROS
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Funding
- Fujiwara Memorial Foundation
- JSPS KAKENHI [JP19K17137, JP16H06280]
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The study shows that inhibition of Na+/Ca2+ exchange by EIPA and MIA can trigger NETotic cell death in neutrophils, indicating a new mechanism of infection-independent NET generation.
In addition to its function of innate immunity against invading pathogens, neutrophil extracellular traps (NETs) promote thrombosis, autoimmune disease, and cancer metastasis; therefore, unnecessary exposure to the triggers of infection-independent NET generation should be avoided. We herein show that inhibition of forward-mode Na+/Ca2+ exchange by amiloride analogs, 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and 5-(N-Methyl-N-isobutyl)amiloride (MIA), triggers NETotic cell death independently of infectious stimuli. Isolated human neutrophils treated with EIPA and MIA undergo NETotic cell death by an increase of intracellular Ca2+ following activation of NADPH oxidase and the resultant upregulation of intracellular ROS. EIPA- and MIA-mediated intracellular Ca2+ increase is attributed to the competitive binding of EIPA and MIA against Na+ to Na+/Ca2+ exchanger 1 (NCX1). These results demonstrate a new mechanism of infection-independent NET generation and implicate NCX1 as a physiologic regulator of intracellular calcium balance and NETotic cell death.
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