Abstract
Production of superoxide anion and other reactive oxygen species (ROS) by neutrophils has a vital role in host defense against microbes. However, over-production can induce cell injury participating to inflammation. Superoxide anion is produced by the phagocyte NADPH oxidase/NOX2, a multicomponent enzyme system consisting of six proteins: two trans-membrane proteins (gp91phox and p22phox) and four soluble cytosolic proteins (p40phox, p67phox, p47phox, and the small G-proteins, Rac1/2). Phosphorylation of p47phox on several serines regulates NADPH oxidase activation. LPS released by gram negative bacteria can enhance or prime neutrophil superoxide production in combination with other agonists such as the bacterial peptide formyl-Met-Leu-Phe (fMLP). Since the pathways involved in LPS-induced priming are not completely understood, we investigated the role of the prolyl cis/trans isomerase Pin1 in this process. Two different Pin1 inhibitors, PiB, and Juglone are able to block LPS-induced priming of ROS production by human neutrophils in a concentration dependent manner. PiB and Juglone did not inhibit LPS-induced CD11b translocation neither CD62L shedding. LPS induced an increase of Pin1 activity in neutrophils similar to TNFα and fMLP. Since the phosphorylation of p47phox on Ser345 is critical for NADPH oxidase up-regulation, we investigated the effect of LPS on this process. Results show that LPS induced the phosphorylation of p47phox mainly on serine 345 and induced the activation of p38MAPKinase and ERK1/2. These results suggest that the prolyl cis/trans isomerase Pin1 may control LPS-induced priming of superoxide production in human neutrophils. Pharmacological targeting of Pin1 could be a valuable approach in sepsis.
Highlights
Polymorphonuclear neutrophils (PMN) are the most abundant immune cells in human blood [1]
We have shown that Pin1 was involved in TNF- and CL097-induced priming of nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase in human neutrophils [18, 19, 33]
Results show that LPS alone had no effect on reactive oxygen species (ROS) production by neutrophils at low concentrations and we found a weak but significant increase in ROS production starting from 1 μg/ml of LPS (Figures 1A,B)
Summary
Polymorphonuclear neutrophils (PMN) are the most abundant immune cells in human blood [1]. PMN are the first circulating cells to reach the inflammatory and infection site [3, 4] They are attracted by a variety of peptides, chemokines and lipids such as. Pin Is Required for LPS-Induced NOX2 Priming the C5a, N-formyl-methionyl-leucyl-phenylalanine (fMLF or fMLP), interleukin 8 (IL-8), LTB4, and platelet activating factor (PAF). They recognize microbes by their TLR receptors, engulf them and release huge number of anti-bacterial agents such as reactive oxygen species (ROS), myeloperoxidase, proteases, glucosidases, and anti-bacterial peptides in order to kill and eliminate microbes [3,4,5,6]. The enzyme responsible for ROS production is the nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase, referred as NOX2 [7, 8]; which produces superoxide anion (O2−), the source of other ROS molecules such as hydrogen peroxide (H2O2) which is used by myeloperoxidase to produce hypochlorous acid (HOCl), all of which cause the destruction and death of pathogens in the phagosome [6,7,8,9]
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