Regulating NETosis: Increasing pH Promotes NADPH Oxidase-Dependent NETosis

Frontiers in Medicine
Meraj A KhanNades Palaniyar

Abstract

Neutrophils migrating from the blood (pH 7.35-7.45) into the surrounding tissues encounter changes in extracellular pH (pHe) conditions. Upon activation of NADPH oxidase 2 (Nox), neutrophils generate large amounts of H+ions reducing the intracellular pH (pHi). Nevertheless, how extracellular pH regulates neutrophil extracellular trap (NET) formation (NETosis) is not clearly established. We hypothesized that increasing pH increases Nox-mediated production of reactive oxygen species (ROS) and neutrophil protease activity, stimulating NETosis. Here, we found that raising pHe(ranging from 6.6 to 7.8; every 0.2 units) increased pHiof both activated and resting neutrophils within 10-20 min (Seminaphtharhodafluor dual fluorescence measurements). Since Nox activity generates H+ions, pHiis lower in neutrophils that are activated compared to resting. We also found that higher pH stimulated Nox-dependent ROS production (R123 generation; flow cytometry, plate reader assay, and imaging) during spontaneous and phorbol myristate acetate-induced NETosis (Sytox Green assays, immunoconfocal microscopy, and quantifying NETs). In neutrophils that are activated and not resting, higher pH stimulated histone H4 cleavage (Western blots) and NETosis. R...Continue Reading

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Citations

Feb 1, 2019·Cell Biochemistry and Function·Yanqiu YouCaijun Zha
Aug 17, 2019·Biomolecules·Mithunan RavindranNades Palaniyar
Jul 1, 2020·Journal of Pineal Research·Somanathapura K NaveenKumarKesturu S Girish
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Aug 17, 2019·Biomolecules·Hussein J Hamam, Nades Palaniyar
Aug 1, 2020·International Journal of Molecular Sciences·Rushikesh Deshpande, Chunbin Zou
Jan 8, 2020·International Journal of Molecular Sciences·Louise InjarabianBenoit S Marteyn
Feb 26, 2019·Frontiers in Immunology·Mohib UddinFrauke Pedersen
Dec 30, 2020·International Journal of Immunopathology and Pharmacology·Liliana Íñiguez-GutiérrezVidal Delgado-Rizo
Apr 6, 2021·Frontiers in Cellular and Infection Microbiology·Jingyi WangMingyun Li
Jun 27, 2021·Microbial Pathogenesis·Zahra Azimzadeh TabriziHamed Mohammadi
Sep 20, 2021·Clinica Chimica Acta; International Journal of Clinical Chemistry·Sanni KumarAnupam Jyoti

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Methods Mentioned

BETA
blood draw
blood
PMA
flow cytometry
confocal microscopy

Software Mentioned

Volocity
Image Studio
GraphPad Prism

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