Chemical Tools for Targeted Amplification of Reactive Oxygen Species in Neutrophils

Abstract

A number of chemical compounds are known, which amplify the availability of reactive oxygen species (ROS) in neutrophils both in vitro and in vivo. They can be roughly classified into NADPH oxidase 2 (NOX2)-dependent and NOX2-independent reagents. NOX2 activation is triggered by protein kinase C agonists (e.g., phorbol esters, transition metal ions), redox mediators (e.g., paraquat) or formyl peptide receptor (FPR) agonists (e.g., aromatic hydrazine derivatives). NOX2-independent mechanisms are realized by reagents affecting glutathione homeostasis (e.g., l-buthionine sulfoximine), modulators of the mitochondrial respiratory chain (e.g., ionophores, inositol mimics, and agonists of peroxisome proliferator-activated receptor γ) and chemical ROS amplifiers [e.g., aminoferrocene-based prodrugs (ABPs)]. Since a number of inflammatory and autoimmune diseases, as well as cancer and bacterial infections, are triggered or enhanced by aberrant ROS production in neutrophils, it is tempting to use ROS amplifiers as drugs for the treatment of these diseases. However, since the known reagents are not cell specific, their application for treatment likely causes systemic enhancement of oxidative stress, leading to severe side effects. Cell-targeted ROS enhancement can be achieved either by using conjugates of ROS amplifiers with ligands binding to receptors expressed on neutrophils (e.g., the GPI-anchored myeloid differentiation marker Ly6G or FPR) or by designing reagents activated by neutrophil function [e.g., phagocytic activity or enzymatic activity of neutrophil elastase (NE)]. Since binding of an artificial ligand to a receptor may trigger or inhibit priming of neutrophils the latter approach has a smaller potential for severe side effects and is probably better suitable for therapy. Here, we review current approaches for the use of ROS amplifiers and discuss their applicability for treatment. As an example, we suggest a possible design of neutrophil-specific ROS amplifiers, which are based on NE-activated ABPs.

Anti-Inflammatory Activity of Oat Beta-Glucans in a Crohn’s Disease Model: Time- and Molar Mass-Dependent Effects

“…Other studies have reported that the active phase of IBD shows a higher concentration of MPO than that observed in the remission phase [50]. Higher MPO concentrations are reported in patients with more severe forms of IBD [51] and in patients with other inflammatory conditions [52,53]. Feeding animals with feed containing beta-glucans, regardless of their molar mass, reduced the colon concentration of MPO and accelerated remission of colitis.…”

NOX2 mediates quiescent handling of dead cell remnants in phagocytes

“…These act as electron donors for endogenous H 2 O 2 and 3 O 2 leading to formation of ROS (HO• and O − 2 ∙) as well as ferrocenium cations. The latter can be reduced back to the aminoferrocene by endogenous bulk reducing agents, such as GSH and NADPH, thereby closing the catalytic cycle [72]. Aminoferrocenes are powerful ROS amplifiers both in vitro and in vivo .…”

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

“…Decreased levels of intracellular glutathione peroxidase (GSH-px), due to impaired GRs activity, leads to neutrophil dysfunction during conditions that are associated with chronic inflammation ( 260 , 261 ). NOX2-independent ROS production in neutrophils is amplified by reagents affecting glutathione homeostasis ( 262 ). The wider impact of circulating SLE neutrophils in the modulation of other leukocyte activation is emphasized by the increased release of NETs containing mitochondrial DNA when compared to healthy donors; this was linked to chronic activation of pDCs and amplification of IFNα production ( 119 , 263 ).…”