Human myeloperoxidase in innate and acquired immunity.

The heme protein myeloperoxidase (MPO) is a major constituent of neutrophils. As a key mediator of the innate immune system, neutrophils are rapidly recruited to inflammatory sites, where they recognize, phagocytose, and inactivate foreign microorganisms. In the newly formed phagosomes, MPO is involved in the creation and maintenance of an alkaline milieu, which is optimal in combatting microbes. Myeloperoxidase is also a key component in neutrophil extracellular traps. These helpful properties are contrasted by the release of MPO and other neutrophil constituents from necrotic cells or as a result of frustrated phagocytosis. Although MPO is inactivated by the plasma protein ceruloplasmin, it can interact with negatively charged components of serum and the extracellular matrix. In cardiovascular diseases and many other disease scenarios, active MPO and MPO-modified targets are present in atherosclerotic lesions and other disease-specific locations. This implies an involvement of neutrophils, MPO, and other neutrophil products in pathogenesis mechanisms. This review critically reflects on the beneficial and harmful functions of MPO against the background of immune response.

https://www.mdpi.com/1422-0067/21/21/8057/pdf

The Dual Role of Myeloperoxidase in Immune Response.

Myeloperoxidase: Growing importance in cancer pathogenesis and potential drug target

The fluorescein-derived dye aminophenyl fluorescein is a suitable tool to detect hypobromous acid (HOBr)-producing activity in eosinophils.

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.

/pdf/discovery-of-novel-potent-reversible-and-irreversible-348k2oj95r.pdf

Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

The heme-containing enzyme myeloperoxidase (MPO) becomes expressed to the cell surface of non-vital polymorphonuclear leukocytes (PMNs) as evidenced by flow cytometry analysis and confocal fluorescence microscopy. While only a very small percentage of freshly isolated cells was able to bind the MPO antibody, PMN suspensions cultured for 36 h or longer time periods contained an increasing number of cells able to interact with these antibodies. Two distinct patterns of fluorescence for the MPO antibodies were observed. Antibodies were localised either in surface patches or distributed over the whole cell body. The latter type dominated in cell samples cultured for more than three days, while the first type was predominantly found in samples cultured for lower time periods. We observed also two peaks for fluorescence distribution by flow cytometry after addition of MPO antibodies to PMNs. Myeloperoxidase was localised at phosphatidylserine epitopes at the surface of non-vital PMNs as evidenced by coincubation with fluorescent MPO antibodies and FITC-labelled annexin V. Myeloperoxidase bound to the outer surface of PMNs uses hydrogen peroxide as a substrate as shown by appearance of an intense chemiluminescence using the impermeable luminescent protein Pholasin. Thus, myeloperoxidase becomes expressed to the surface of non-vital polymorphonuclear leukocytes colocalised with phosphatidylserine that may indicate a role of myeloperoxidase in apoptosis of PMNs.

/pdf/non-vital-polymorphonuclear-leukocytes-express-l2qqukdr2c.pdf

Non-vital polymorphonuclear leukocytes express myeloperoxidase on their surface.

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Non-vital polymorphonuclear leukocytes express myeloperoxidase on their surface.