Macrophage Activation Includes High Intracellular Myeloperoxidase Activity

doi:10.1006/bbrc.2002.6724

Biochemical and Biophysical Research Communications

Volume 292, Issue 4, 12 April 2002, Pages 869-873

https://doi.org/10.1006/bbrc.2002.6724 Get rights and content

Abstract

Macrophages recovered from the peritoneum of mice, 48 h after concanavalin A administration, are primed and have a higher content of myeloperoxidase (MPO) than resident cells. The increase in MPO content is accompanied by an increased capability of macrophages generate hypochlorous acid and increased peroxidase activity. Contrary to the common sense, neutrophils is not the source of the MPO activity found in primed macrophages since macrophages recovered from mice treated with antigranulocyte antibody preserve the peroxidase activity. Given the broad spectrum of action of MPO, the preservation of MPO in primed macrophages might play a special role in the killing of pathogens and inflammation.

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Cited by (67)

Myeloperoxidase: Growing importance in cancer pathogenesis and potential drug target
2022, Pharmacology and Therapeutics
Citation Excerpt :
During monocyte-to-macrophage differentiation, the expression of MPO is generally terminated (reviewed in Van Der Veen et al., 2009). However, MPO can be found in macrophage subpopulations (e.g. resident tissue macrophages such as Kupffer cells) (Brown, Brunt, & Heinecke, 2001), peritoneal macrophages (Rodrigues, Rodriguez, Russo, & Campa, 2002) and microglia (Nagra et al., 1997), as well as in tissue infiltrating macrophages in inflammatory diseases such as atherosclerosis (Malle et al., 2000) and multiple sclerosis (Nagra et al., 1997). MPO positive macrophages mainly acquired MPO protein by phagocytosis of apoptotic neutrophils or by uptake of extracellular MPO through the mannose receptor (Shepherd & Hoidal, 1990).
Myeloperoxidase is a heme-peroxidase which makes up approximately 5% of the total dry cell weight of neutrophils where it is predominantly found in the primary (azurophilic) granules. Other cell types, such as monocytes and certain macrophage subpopulations also contain myeloperoxidase, but to a much lesser extent. Initially, the function of myeloperoxidase had been mainly associated with its ability as a catalyzer of reactive oxidants that help to clear pathogens. However, over the past years non-canonical functions of myeloperoxidase have been described both in health and disease. Attention has been specially focused on inflammatory diseases, in which an exacerbate infiltration of leukocytes can favor a poorly-controlled production and release of myeloperoxidase and its oxidants. There is compelling evidence that myeloperoxidase derived oxidants contribute to tissue damage and the development and propagation of acute and chronic vascular inflammation. Recently, neutrophils have attracted much attention within the large diversity of innate immune cells that are part of the tumor microenvironment. In particular, neutrophil-derived myeloperoxidase may play an important role in cancer development and progression. This review article aims to provide a comprehensive overview of the roles of myeloperoxidase in the development and progression of cancer. We propose future research approaches and explore prospects of inhibiting myeloperoxidase as a strategy to fight against cancer.
SARS-CoV2 vertical transmission with adverse effects on the newborn revealed through integrated immunohistochemical, electron microscopy and molecular analyses of Placenta
2020, EBioMedicine
. The occurrence of trans-placental transmission of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection remains highly debated. Placental positivity for SARS-CoV-2 has been reported in selected cases, but infection or virus-associated disease of fetal tissues or newborns remains to be demonstrated.
We screened for SARS-CoV-2 spike (S) protein expression placentas from 101 women who delivered between February 7 and May 15, 2020, including 15 tested positive for SARS-CoV-2 RNA, 34 tested negative, and 52 not evaluated as they did not meet testing criteria (32), or delivered before COVID-19 pandemic declaration (20). Immunostain for SARS-CoV-2 nucleocapsid (N) was performed in the placentas of all COVID-19 positive women. One placenta resulted positive for the SARS-CoV-2 S and N proteins, which was further studied by RNA-in situ hybridization and RT-PCR for S transcripts, and by electron microscopy. A comprehensive immunohistochemical and immunofluorescence analysis of the placental inflammatory infiltrate completed the investigations.
SARS-CoV-2 S and N proteins were strongly expressed in the placenta of a COVID-19 pregnant woman whose newborn tested positive for viral RNA and developed COVID-19 pneumonia soon after birth. SARS-CoV-2 antigens, RNA and/or particles morphologically consistent with coronavirus were identified in villous syncytiotrophoblast, endothelial cells, fibroblasts, in maternal macrophages, and in Hofbauer cells and fetal intravascular mononuclear cells. The placenta intervillous inflammatory infiltrate consisted of neutrophils and monocyte-macrophages expressing activation markers. Absence of villitis was associated with an increase in the number of Hofbauer cells, which expressed PD-L1. Scattered neutrophil extracellular traps (NETs) were identified by immunofluorescence.
We provide first-time evidence for maternal-fetal transmission of SARS-CoV-2, likely propagated by circulating virus-infected fetal mononuclear cells. Placenta infection was associated with recruitment of maternal inflammatory cells in the intervillous space, without villitis. PD-L1 expression in syncytiotrophoblast and Hofbaeur cells, together with limited production of NETs, may have prevented immune cell-driven placental damage, ensuring sufficient maternal-fetus nutrient exchanges.
The acid response network of Staphylococcus aureus
2020, Current Opinion in Microbiology
Citation Excerpt :
On the one hand, bacteria encounter complex environments where both stressors coexist. Upon macrophage phagocytosis, vacuolar ATPase functions to decrease phagosomal pH to create an acidic environment, while intracellular myeloperoxidase produces reactive oxygen intermediates including hypochlorous acid (HOCl) from chloride ions and hydrogen peroxide [45,46]. On the other hand, acid stress is able to induce endogenous ROS generation.
Staphylococcus aureus colonizes or causes infection in a multitude of niches within a mammalian host. Many of these niches are acidic, yet specific pH resistance mechanisms that facilitate survival have not been thoroughly investigated. This review discusses recent studies documenting known acid resistance mechanisms in S. aureus and other staphylococcal species. However, studies that clearly define the regulation of the acid resistance regulon and potential interactions with weak organic acids in specific niches of the host including the skin and gut are yet to be defined.
Lipolysis modulates the biosynthesis of inflammatory lipid mediators derived from linoleic acid in adipose tissue of periparturient dairy cows
2020, Journal of Dairy Science
Oxidized linoleic acid metabolites (OXLAM) are products of adipocyte lipolysis with the potential to modulate adipose tissue (AT) lipid metabolism and inflammation. In periparturient cows, linoleic acid is preferentially mobilized from AT during lipolysis by hormone-sensitive lipase (HSL) compared with other polyunsaturated fatty acids. Enzymatic and nonenzymatic reactions generate OXLAM from linoleic acid. Among OXLAM, 9-, 10-, and 12-hydroxy-octadecadienoic acids (HODE) are associated with pro-inflammatory responses, whereas 9- and 13-oxo-octadecadienoic acids (oxoODE) and 13-HODE can facilitate inflammation resolution and promote lipogenesis. This study evaluated the effect of HSL activity on OXLAM biosynthesis using subcutaneous AT explants collected from multiparous dairy cows at 10 d before and again at 10 and 24 d after calving. Explants were treated for 3 h without or with the β-adrenergic agonist isoproterenol (ISO; 1 µM; MilliporeSigma, Burlington, MA) to induce HSL activity. The contribution of HSL to OXLAM biosynthesis was determined by inhibiting its activity with CAY10499 (2 µM; Cayman Chemical, Ann Arbor, MI). After treatments, media and explants were collected for lipidomic analysis using HPLC–tandem mass spectroscopy. Results indicated that ISO increased the biosynthesis of 9-, 12-, and 13-HODE and 9-oxoODE, and this effect was reduced at 24 d after calving. Inhibiting HSL activity partially reversed ISO effects on HODE and 9-oxoODE. Our ex vivo model demonstrated for the first time a direct effect of HSL activity on the biosynthesis of OXLAM in AT, especially at 10 d before and 10 d after calving. The biosynthesis of anti-inflammatory OXLAM is limited during the first weeks after parturition and may promote AT inflammation and lipolytic responses to negative energy balance. These results indicate that HSL activity releases linoleic acid for OXLAM biosynthesis in concentrations of a magnitude that may bypass the need for the activation of phospholipases linked with the inflammatory cascade and thus supports, in part, lipolysis-driven inflammation within AT of periparturient cows.
Myeloperoxidase – A bridge linking inflammation and oxidative stress with cardiovascular disease
2019, Clinica Chimica Acta
Citation Excerpt :
It has been suggested that small amounts of MPO escape from the neutrophils (as proMPO monomers) and are released into the extracellular space [38]. Although MPO is predominantly found in neutrophils and monocytes, other cells including CD4+ and CD8+ lymphocytes [39], resident tissue macrophages such as Kupffer cells [40], peritoneal macrophages [41], and microglia [42], infiltrating macrophages in inflammatory diseases including atherosclerotic lesions [43] and vasculitis [44] show MPO activity. MPO activity has been detected in prostate tissue [45], neurons [46] and astrocytes [32].
Myeloperoxidase (MPO) is a member of the superfamily of heme peroxidases that is mainly expressed in neutrophils and monocytes. MPO-derived reactive species play a key role in neutrophil antimicrobial activity and human defense against various pathogens primarily by participating in phagocytosis. Elevated MPO levels in circulation are associated with inflammation and increased oxidative stress. Multiple lines of evidence suggest an association between MPO and cardiovascular disease (CVD) including coronary artery disease, congestive heart failure, arterial hypertension, pulmonary arterial hypertension, peripheral arterial disease, myocardial ischemia/reperfusion-related injury, stroke, cardiac arrhythmia and venous thrombosis. Elevated MPO levels are associated with a poor prognosis including increased risk for overall and CVD-related mortality. Elevated MPO may signify an increased risk for CVD for at least 2 reasons. First, low-grade inflammation and increased oxidative stress coexist with many metabolic abnormalities and comorbidities and consequently an elevated MPO level may represent an increased cardiometabolic risk in general. Second, MPO produces a large number of highly reactive species which can attack, destroy or modify the function of every known cellular component. The most common MPO actions relevant to CVD are generation of dysfunctional lipoproteins with an increased atherogenicity potential, reduced NO availability, endothelial dysfunction, impaired vasoreactivity and atherosclerotic plaque instability. These actions strongly suggest that MPO is directly involved in the pathophysiology of CVD. In this regard MPO may be seen as a mediator or an instrument through which inflammation promotes CVD at molecular and cellular level. Clinical value of MPO therapeutic inhibition remains to be tested.
Intestinal toxicity of oral warfarin intake in rats
2016, Food and Chemical Toxicology
Citation Excerpt :
Increases of myeloperoxidase activity in tissue homogenates reflect neutrophil activity, as this enzyme is the major aspect of effector mechanisms of these leukocytes (Nathan, 2006). However, contribution of macrophages to the MPO activity could not be excluded as these cells produce this enzyme as well (Rodrigues et al., 2002). Increases in MPO represent, most probably, means of protection of intestinal tissue from intestinal bacteria which might reach injured tissue.
Though warfarin is extensively used in the prevention and treatment of thromboembolic processes in humans, adverse effects of warfarin therapy have been recognized. Intestinal hemorrhage is one of the hazards of anticoagulant therapy, but the mechanisms of warfarin toxicity are virtually unknown. In this work, the effects of 30 days oral warfarin (0.35 mg/l and 3.5 mg/l) intake on rat’s gut were examined. Both doses resulted in prolongation of prothrombin time. Systemic effects of higher warfarin dose (increases in plasma AST, proteinuria, hematuria, changes in peripheral blood hematological parameters) were seen. Warfarin intake resulted in histologically evident tissue damage, leukocyte infiltration and intestinal inflammation [increases in myeloperoxidase activity, malondialdehyde content, superoxide dismutase and catalase activity, proinflammatory cytokine (IFN-γ, IL-17) concentrations in intestinal homogenates]. In contrast, suppression of gut-draining mesenteric lymph node (MLN) cell activity [proliferation responsiveness, production of IFN-γ and IL-17 to T lymphocyte mitogen Concanavalin A stimulation] was noted. Inhibition of regulatory cytokine IL-10 production by MLN cells, suggests commitment of MLN to the suppression of all inflammatory activities and creation of the microenvironment which is non-permissive for induction of potentially harmful immune response. These novel findings indicate the need of staying alert for (adverse) effects of warfarin therapy.

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Biochemical and Biophysical Research Communications

Abstract

References (26)

Inside the neutrophil phagosome: Oxidants, myeloperoxidase and bacterial killing

Blood

Effects of concanavalin A and pokeweed mitogen in vivo on mouse peritoneal macrophages

Exp. Cell Res.

A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding

Anal. Biochem.

Mice lacking myeloperoxidase are more susceptible to experimental autoimmune encephalomyelitis

J. Neuroimmunol.

NADPH oxidase: An update

Blood.

Nitric oxide modulates the catalytic activity of myeloperoxidase

J. Biol. Chem.

Nitric oxide is a physiological substrate for mammalian peroxidases

J. Biol. Chem.

Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease

Exp. Neurol.

Mechanisms generating functionally heterogeneous macrophages: Chaos revisited

J. Leukocyte Biol.

Regulation of cytokine gene expression by reactive oxygen and reactive nitrogen intermediates

J. Leukocyte Biol.

Nuclear factor κB: An oxidative stress-responsive transcription factor of eukaryotic cells (review)

Free Radicals Res. Comm.

Production of the superoxide adduct of myeloperoxidase (compound III) by stimulated human neutrophils and its reactivity with hydrogen peroxide and chloride

Biochem. J.

Cited by (67)

Myeloperoxidase: Growing importance in cancer pathogenesis and potential drug target

SARS-CoV2 vertical transmission with adverse effects on the newborn revealed through integrated immunohistochemical, electron microscopy and molecular analyses of Placenta

The acid response network of Staphylococcus aureus

Lipolysis modulates the biosynthesis of inflammatory lipid mediators derived from linoleic acid in adipose tissue of periparturient dairy cows

Myeloperoxidase – A bridge linking inflammation and oxidative stress with cardiovascular disease

Intestinal toxicity of oral warfarin intake in rats

Regular ArticleMacrophage Activation Includes High Intracellular Myeloperoxidase Activity

Abstract

Blood

Exp. Cell Res.

Anal. Biochem.

J. Neuroimmunol.

Blood.

J. Biol. Chem.

J. Biol. Chem.

Exp. Neurol.

Mechanisms generating functionally heterogeneous macrophages: Chaos revisited

J. Leukocyte Biol.

Regulation of cytokine gene expression by reactive oxygen and reactive nitrogen intermediates

J. Leukocyte Biol.

Nuclear factor κB: An oxidative stress-responsive transcription factor of eukaryotic cells (review)

Free Radicals Res. Comm.

Production of the superoxide adduct of myeloperoxidase (compound III) by stimulated human neutrophils and its reactivity with hydrogen peroxide and chloride

Biochem. J.

Regular Article
Macrophage Activation Includes High Intracellular Myeloperoxidase Activity