Killing activity of neutrophils is mediated through activation of proteases by K+ flux

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

“…These cells express very large amounts of gp91 phox , now also called Nox2, along with its regulatory subunits p47 phox , p67 phox , p40 phox and Rac2, reviewed in [1,2]. It can be calculated that the concentration of ROS produced in the phagosome is extremely high, probably in the molar range [3]. In addition, myeloperoxidase (MPO) is secreted into the phagosome where it converts H 2 O 2 (produced by Nox2) plus chloride into HOCl; the latter has a direct microbicidal effect [4,5] (although surprisingly, MPO-deficient individuals do not suffer from markedly increased rates or apparent severity of infections [6]).…”

“…In addition, macrophages (but possibly not neutrophils) produce large production of NO during phagocytosis; when NO reacts with superoxide, it generates the highly cytotoxic chemical species peroxinitrite (HONO) [7]. The activity of the phagocyte NADPH-oxidase also triggers opening of proton [8][9][10][11] and possibly potassium channels [3], that are proposed to change the ionic environment of the phagosome thereby activating microbicidal proteases and contributing to microbial killing [3]. Regardless of the precise mechanisms, it is clear from the inherited condition chronic granulomatous disease (CGD) that mutations resulting in defects in ROS generation by the respiratory burst oxidase are associated with an inability of phagocytes to kill bacteria and other microbes [12], convincingly demonstrating a role for the Nox2 system in innate immunity mediated by professional phagocytes.…”

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…Therefore, cellular actions of NOX/DUOX may also include ROSindependent mechanisms. Similarly, the antimicrobial action of NOX2 in phagocytes not only involves ROS production, but is also related to NOX-catalyzed extrusion of K + into the phagosomal vacuole through BKCa channels, which promotes the activation of neutral proteases (23).…”

“…However, compared to the dramatic consequences of NADPH oxidase deficiency (due to mutations in NOX2 or associated proteins), genetic deficiencies in either MPO or EPO are relatively non-consequential and do not result in significant antimicrobial or antifungal defects (26). This suggests that NOX2-mediated antimicrobial actions must also include mechanisms that are independent of heme peroxidases (23).…”

Changing world of neutrophils

“…Killing and degradation of the microorganism proceed in the small phagosomal space in a concentrated action of the involved ingredients, although the contribution of the individual factors may vary depending on the type of microorganism [89,91]. The molecular details of these processes have been worked out and summarized in recent excellent reviews [11,58,66,75,77,78,80,102,115].…”