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Kidney International Mar 2024
Topics: Humans; Antibodies, Antineutrophil Cytoplasmic; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Peroxidase
PubMed: 38388102
DOI: 10.1016/j.kint.2023.10.008 -
The Journal of Clinical Investigation Dec 2022BackgroundAntineutrophil cytoplasmic autoantibody-associated (ANCA-associated) vasculitidies (AAV) are life-threatening systemic autoimmune conditions. ANCAs directed...
BackgroundAntineutrophil cytoplasmic autoantibody-associated (ANCA-associated) vasculitidies (AAV) are life-threatening systemic autoimmune conditions. ANCAs directed against proteinase 3 (PR3) or myeloperoxidase (MPO) bind their cell surface-presented antigen, activate neutrophils, and cause vasculitis. An imbalance between PR3 and its major inhibitor α1-antitrypsin (AAT) was proposed to underlie PR3- but not MPO-AAV. We measured AAT and PR3 in healthy individuals and patients with AAV and studied protective AAT effects pertaining to PR3- and MPO-ANCA.MethodsPlasma and blood neutrophils were assessed for PR3 and AAT. WT, mutant, and oxidation-resistant AAT species were produced to characterize AAT-PR3 interactions by flow cytometry, immunoblotting, fluorescence resonance energy transfer assays, and surface plasmon resonance measurements. Neutrophil activation was measured using the ferricytochrome C assay and AAT methionine-oxidation by Parallel Reaction Monitoring.ResultsWe found significantly increased PR3 and AAT pools in patients with both PR3- and MPO-AAV; however, only in PR3-AAV did the PR3 pool correlate with the ANCA titer, inflammatory response, and disease severity. Mechanistically, AAT prevented PR3 from binding to CD177, thereby reducing neutrophil surface antigen for ligation by PR3-ANCA. Active patients with PR3-AAV showed critical methionine-oxidation in plasma AAT that was recapitulated by ANCA-activated neutrophils. The protective PR3-related AAT effects were compromised by methionine-oxidation in the AAT reactive center loop but preserved when 2 critical methionines were substituted with valine and leucine.ConclusionPathogenic differences between PR3- and MPO-AAV are related to AAT regulation of membrane-PR3, attenuating neutrophil activation by PR3-ANCA rather than MPO-ANCA. Oxidation-resistant AAT could serve as adjunctive therapy in PR3-AAV.FUNDINGThis work was supported by KE 576/10-1 from the Deutsche Forschungsgemeinschaft, SCHR 771/8-1 from the Deutsche Forschungsgemeinschaft, grant 394046635 - SFB 1365 from the Deutsche Forschungsgemeinschaft, and ECRC grants.
Topics: Humans; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Giant Cell Arteritis; Methionine; Mucocutaneous Lymph Node Syndrome; Myeloblastin; Neutrophil Activation; Peroxidase; alpha 1-Antitrypsin
PubMed: 36125911
DOI: 10.1172/JCI160089 -
JACC. Heart Failure Jul 2023Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Systemic microvascular dysfunction and inflammation are postulated to play a pathophysiologic role in heart failure with preserved ejection fraction (HFpEF).
OBJECTIVES
This study aimed to identify biomarker profiles associated with clinical outcomes in HFpEF and investigate how inhibition of the neutrophil-derived reactive oxygen species-producing enzyme, myeloperoxidase, affects these biomarkers.
METHODS
Using supervised principal component analyses, the investigators assessed the associations between baseline plasma proteomic Olink biomarkers and clinical outcomes in 3 independent observational HFpEF cohorts (n = 86, n = 216, and n = 242). These profiles were then compared with the biomarker profiles discriminating patients treated with active drug vs placebo in SATELLITE (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure), a double-blind randomized 3-month trial evaluating safety and tolerability of the myeloperoxidase inhibitor AZD4831 in HFpEF (n = 41). Pathophysiological pathways were inferred from the biomarker profiles by interrogation of the Ingenuity Knowledge Database.
RESULTS
TNF-R1, TRAIL-R2, GDF15, U-PAR, and ADM were the top individual biomarkers associated with heart failure hospitalization or death, and FABP4, HGF, RARRES2, CSTB, and FGF23 were associated with lower functional capacity and poorer quality of life. AZD4831 downregulated many markers (most significantly CDCP1, PRELP, CX3CL1, LIFR, VSIG2). There was remarkable consistency among pathways associated with clinical outcomes in the observational HFpEF cohorts, the top canonical pathways being associated with tumor microenvironments, wound healing signaling, and cardiac hypertrophy signaling. These pathways were predicted to be downregulated in AZD4831 relative to placebo-treated patients.
CONCLUSIONS
Biomarker pathways that were most strongly associated with clinical outcomes were also the ones reduced by AZD4831. These results support the further investigation of myeloperoxidase inhibition in HFpEF.
Topics: Humans; Antigens, Neoplasm; Biomarkers; Cell Adhesion Molecules; Heart Failure; Peroxidase; Proteomics; Quality of Life; Stroke Volume
PubMed: 37140510
DOI: 10.1016/j.jchf.2023.03.002 -
Biosensors Dec 2022As a rapid and simple method for the detection of multiple targets, immunoassay has attracted extensive attention due to the merits of high specificity and sensitivity.... (Review)
Review
As a rapid and simple method for the detection of multiple targets, immunoassay has attracted extensive attention due to the merits of high specificity and sensitivity. Notably, enzyme-linked immunosorbent assay (ELISA) is a widely used immunoassay, which can provide high detection sensitivity since the enzyme labels can promote the generation of catalytically amplified readouts. However, the natural enzyme labels usually suffer from low stability, high cost, and difficult storage. Inspired by the advantages of superior and tunable catalytic activities, easy preparation, low cost, and high stability, nanozymes have arisen to replace the natural enzymes in immunoassay; they also possess equivalent sensitivity and selectivity, as well as robustness. Up to now, various kinds of nanozymes, including mimic peroxidase, oxidase, and phosphatase, have been incorporated to construct immunosensors. Herein, the development of immunoassays based on nanozymes with various types of detection signals are highlighted and discussed in detail. Furthermore, the challenges and perspectives of the design of novel nanozymes for widespread applications are discussed.
Topics: Immunoassay; Nanostructures; Biosensing Techniques; Peroxidase; Enzyme-Linked Immunosorbent Assay; Catalysis
PubMed: 36551085
DOI: 10.3390/bios12121119 -
Journal of Leukocyte Biology Oct 2022The text extracted from the initial paragraph of a paper coauthored by Zanvil Cohn, one of the pioneers in the study of leukocyte biology, highlights two phenomena that...
The text extracted from the initial paragraph of a paper coauthored by Zanvil Cohn, one of the pioneers in the study of leukocyte biology, highlights two phenomena that stimulated investigations of innate immunity in the middle of the last century, namely phagocytosis and intracellular antimicrobial activity. Although many features of phagocytosis have been characterized since that time, fundamental aspects of the antimicrobial action of neutrophils remain unknown. The report by Ashby et al. provides a refined and nuanced look at the interface between an ingested microbe, Staphylococcus aureus, and HOCl generated by the myeloperoxidase (MPO)-H O -chloride system in neutrophil phagosomes and represents a holistic approach to the analysis of bactericidal mechanisms that recognizes contributions from both phagocyte and its ingested prey.
Topics: Anti-Bacterial Agents; Chlorides; Hypochlorous Acid; Neutrophils; Peroxidase; Phagocytosis; Phagosomes
PubMed: 35929044
DOI: 10.1002/JLB.4CE0422-232R -
Biomolecules Jul 2021Nanomaterial-mediated cancer therapeutics is a fast developing field and has been utilized in potential clinical applications. However, most effective therapies, such as... (Review)
Review
Nanomaterial-mediated cancer therapeutics is a fast developing field and has been utilized in potential clinical applications. However, most effective therapies, such as photodynamic therapy (PDT) and radio therapy (RT), are strongly oxygen-dependent, which hinders their practical applications. Later on, several strategies were developed to overcome tumor hypoxia, such as oxygen carrier nanomaterials and oxygen generated nanomaterials. Among these, oxygen species generation on nanozymes, especially catalase (CAT) mimetic nanozymes, convert endogenous hydrogen peroxide (HO) to oxygen (O) and peroxidase (POD) mimetic nanozymes converts endogenous HO to water (HO) and reactive oxygen species (ROS) in a hypoxic tumor microenvironment is a fascinating approach. The present review provides a detailed examination of past, present and future perspectives of POD mimetic nanozymes for effective oxygen-dependent cancer phototherapeutics.
Topics: Animals; Biomimetic Materials; Humans; Nanostructures; Neoplasms; Oxygen; Peroxidase; Photochemotherapy; Tumor Hypoxia; Tumor Microenvironment
PubMed: 34356639
DOI: 10.3390/biom11071015 -
Redox Biology Nov 2023Myeloperoxidase (MPO) is one of the most abundant proteins in neutrophil granules. It catalyzes the production of reactive oxygen species, which are important in...
Myeloperoxidase (MPO) is one of the most abundant proteins in neutrophil granules. It catalyzes the production of reactive oxygen species, which are important in inflammation and immune defense. MPO also binds to several proteins, lipids, and DNA to alter their function. MPO is present at the feto-maternal interface during pregnancy, where neutrophils are abundant. In this study, we determined the effect of MPO on JEG-3 human choriocarcinoma cells as a model of extravillous trophoblasts (EVTs) during early pregnancy. We found that MPO was internalized by JEG-3 cells and localized to the cytoplasm and nuclei. MPO internalization and activity enhanced JEG-3 cell migration and invasion, whereas this effect was impaired by pre-treating cells with heparin, to block cellular uptake, and MPO-activity inhibitor 4-ABAH. This study identifies a novel mechanism for the effect of MPO on EVT function during normal pregnancy and suggests a potential role of MPO in abnormal pregnancies.
Topics: Female; Humans; Pregnancy; Cell Line, Tumor; Choriocarcinoma; Peroxidase; Proteins; Trophoblasts
PubMed: 37776707
DOI: 10.1016/j.redox.2023.102885 -
Nature Communications Aug 2022The mechanisms linking systemic infection to hyperinflammation and immune dysfunction in sepsis are poorly understood. Extracellular histones promote sepsis pathology,...
The mechanisms linking systemic infection to hyperinflammation and immune dysfunction in sepsis are poorly understood. Extracellular histones promote sepsis pathology, but their source and mechanism of action remain unclear. Here, we show that by controlling fungi and bacteria captured by splenic macrophages, neutrophil-derived myeloperoxidase attenuates sepsis by suppressing histone release. In systemic candidiasis, microbial capture via the phagocytic receptor SIGNR1 neutralizes myeloperoxidase by facilitating marginal zone infiltration and T cell death-dependent histone release. Histones and hyphae induce cytokines in adjacent CD169 macrophages including G-CSF that selectively depletes mature Ly6G neutrophils by shortening their lifespan in favour of immature Ly6G neutrophils with a defective oxidative burst. In sepsis patient plasma, these mediators shorten mature neutrophil lifespan and correlate with neutrophil mortality markers. Consequently, high G-CSF levels and neutrophil lifespan shortening activity are associated with sepsis patient mortality. Hence, by exploiting phagocytic receptors, pathogens degrade innate and adaptive immunity through the detrimental impact of downstream effectors on neutrophil lifespan.
Topics: Granulocyte Colony-Stimulating Factor; Histones; Humans; Longevity; Macrophages; Neutrophils; Peroxidase; Sepsis; T-Lymphocytes
PubMed: 35945238
DOI: 10.1038/s41467-022-32320-1 -
Applied Microbiology and Biotechnology May 2021Aryl-alcohol oxidases (AAOs) are FAD-containing enzymes that oxidize a broad range of aromatic as well as aliphatic allylic alcohols to aldehydes. Their broad substrate... (Review)
Review
Aryl-alcohol oxidases (AAOs) are FAD-containing enzymes that oxidize a broad range of aromatic as well as aliphatic allylic alcohols to aldehydes. Their broad substrate spectrum accompanied by the only need for molecular oxygen as cosubstrate and production of hydrogen peroxide as sole by-product makes these enzymes very promising biocatalysts. AAOs were used in the synthesis of flavors, fragrances, and other high-value-added compounds and building blocks as well as in dye decolorization and pulp biobleaching. Furthermore, AAOs offer a huge potential as efficient suppliers of hydrogen peroxide for peroxidase- and peroxygenase-catalyzed reactions. A prerequisite for application as biocatalysts at larger scale is the production of AAOs in sufficient amounts. Heterologous expression of these predominantly fungal enzymes is, however, quite challenging. This review summarizes different approaches aiming at enhancing heterologous expression of AAOs and gives an update on substrates accepted by these promising enzymes as well as potential fields of their application. KEY POINTS: • Aryl-alcohol oxidases (AAOs) supply ligninolytic peroxidases with HO. • AAOs accept a broad spectrum of aromatic and aliphatic allylic alcohols. • AAOs are potential biocatalysts for the production of high-value-added bio-based chemicals.
Topics: Alcohol Oxidoreductases; Alcohols; Fungi; Hydrogen Peroxide; Lignin; Peroxidase; Peroxidases
PubMed: 33997930
DOI: 10.1007/s00253-021-11337-4 -
Acta Neuropathologica Communications Mar 2022Neutrophil accumulation is a well-established feature of Alzheimer's disease (AD) and has been linked to cognitive impairment by modulating disease-relevant...
INTRODUCTION
Neutrophil accumulation is a well-established feature of Alzheimer's disease (AD) and has been linked to cognitive impairment by modulating disease-relevant neuroinflammatory and vascular pathways. Neutrophils express high levels of the oxidant-generating enzyme myeloperoxidase (MPO), however there has been controversy regarding the cellular source and localisation of MPO in the AD brain.
MATERIALS AND METHODS
We used immunostaining and immunoassays to quantify the accumulation of neutrophils in human AD tissue microarrays and in the brains of APP/PS1 mice. We also used multiplexed immunolabelling to define the presence of NETs in AD.
RESULTS
There was an increase in neutrophils in AD brains as well as in the murine APP/PS1 model of AD. Indeed, MPO expression was almost exclusively confined to S100A8-positive neutrophils in both human AD and murine APP/PS1 brains. The vascular localisation of neutrophils in both human AD and mouse models of AD was striking and driven by enhanced neutrophil adhesion to small vessels. We also observed rare infiltrating neutrophils and deposits of MPO around plaques. Citrullinated histone H3, a marker of neutrophil extracellular traps (NETs), was also detected in human AD cases at these sites, indicating the presence of extracellular MPO in the vasculature. Finally, there was a reduction in the endothelial glycocalyx in AD that may be responsible for non-productive neutrophil adhesion to the vasculature.
CONCLUSION
Our report indicates that vascular changes may drive neutrophil adhesion and NETosis, and that neutrophil-derived MPO may lead to vascular oxidative stress and be a relevant therapeutic target in AD.
Topics: Alzheimer Disease; Animals; Brain; Extracellular Traps; Humans; Mice; Neutrophils; Peroxidase
PubMed: 35331340
DOI: 10.1186/s40478-022-01347-2