Editorial

4 pages, 587 KiB

Open AccessEditorial

by Tamara Ortiz-Cerda, Kangzhe Xie, Albaraa Mojadadi and Paul K. Witting

Int. J. Mol. Sci. 2023, 24(9), 7725; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097725 - 23 Apr 2023

Cited by 3 | Viewed by 1257

Innate and adaptive immune responses comprise a complex network of protein–protein and protein–cell interactions that regulates commensal flora and protects organisms from foreign pathogens and transformed (proliferating) host cells under physiological conditions such as pregnancy, growth and development as well as formulating a [...] Read more.

Innate and adaptive immune responses comprise a complex network of protein–protein and protein–cell interactions that regulates commensal flora and protects organisms from foreign pathogens and transformed (proliferating) host cells under physiological conditions such as pregnancy, growth and development as well as formulating a response pathological challenge [...] Full article

(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)

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Research

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22 pages, 3821 KiB

Open AccessArticle

Myeloperoxidase-Derived 2-Chlorohexadecanal Is Generated in Mouse Heart during Endotoxemia and Induces Modification of Distinct Cardiomyocyte Protein Subsets In Vitro

by Jürgen Prasch, Eva Bernhart, Helga Reicher, Manfred Kollroser, Gerald N. Rechberger, Chintan N. Koyani, Christopher Trummer, Lavinia Rech, Peter P. Rainer, Astrid Hammer, Ernst Malle and Wolfgang Sattler

Int. J. Mol. Sci. 2020, 21(23), 9235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239235 - 03 Dec 2020

Cited by 8 | Viewed by 2255

Abstract

Sepsis is a major cause of mortality in critically ill patients and associated with cardiac dysfunction, a complication linked to immunological and metabolic aberrations. Cardiac neutrophil infiltration and subsequent release of myeloperoxidase (MPO) leads to the formation of the oxidant hypochlorous acid (HOCl) [...] Read more.

Sepsis is a major cause of mortality in critically ill patients and associated with cardiac dysfunction, a complication linked to immunological and metabolic aberrations. Cardiac neutrophil infiltration and subsequent release of myeloperoxidase (MPO) leads to the formation of the oxidant hypochlorous acid (HOCl) that is able to chemically modify plasmalogens (ether-phospholipids) abundantly present in the heart. This reaction gives rise to the formation of reactive lipid species including aldehydes and chlorinated fatty acids. During the present study, we tested whether endotoxemia increases MPO-dependent lipid oxidation/modification in the mouse heart. In hearts of lipopolysaccharide-injected mice, we observed significantly higher infiltration of MPO-positive cells, increased fatty acid content, and formation of 2-chlorohexadecanal (2-ClHDA), an MPO-derived plasmalogen modification product. Using murine HL-1 cardiomyocytes as in vitro model, we show that exogenously added HOCl attacks the cellular plasmalogen pool and gives rise to the formation of 2-ClHDA. Addition of 2-ClHDA to HL-1 cardiomyocytes resulted in conversion to 2-chlorohexadecanoic acid and 2-chlorohexadecanol, indicating fatty aldehyde dehydrogenase-mediated redox metabolism. However, a recovery of only 40% indicated the formation of non-extractable (protein) adducts. To identify protein targets, we used a clickable alkynyl analog, 2-chlorohexadec-15-yn-1-al (2-ClHDyA). After Huisgen 1,3-dipolar cycloaddition of 5-tetramethylrhodamine azide (N₃-TAMRA) and two dimensional-gel electrophoresis (2D-GE), we were able to identify 51 proteins that form adducts with 2-ClHDyA. Gene ontology enrichment analyses revealed an overrepresentation of heat shock and chaperone, energy metabolism, and cytoskeletal proteins as major targets. Our observations in a murine endotoxemia model demonstrate formation of HOCl-modified lipids in the heart, while pathway analysis in vitro revealed that the chlorinated aldehyde targets specific protein subsets, which are central to cardiac function. Full article

(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)

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22 pages, 4549 KiB

Open AccessArticle

Nitroxides Mitigate Neutrophil-Mediated Damage to the Myocardium after Experimental Myocardial Infarction in Rats

by Mary El Kazzi, Han Shi, Sally Vuong, Xiaosuo Wang, Belal Chami, Yuyang Liu, Benjamin S. Rayner and Paul K. Witting

Int. J. Mol. Sci. 2020, 21(20), 7650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207650 - 16 Oct 2020

Cited by 4 | Viewed by 2909

Abstract

Reperfusion therapy increases survival post-acute myocardial infarction (AMI) while also stimulating secondary oxidant production and immune cell infiltration. Neutrophils accumulate within infarcted myocardium within 24 h post-AMI and release myeloperoxidase (MPO) that catalyses hypochlorous acid (HOCl) production while increasing oxidative stress and inflammation, [...] Read more.

Reperfusion therapy increases survival post-acute myocardial infarction (AMI) while also stimulating secondary oxidant production and immune cell infiltration. Neutrophils accumulate within infarcted myocardium within 24 h post-AMI and release myeloperoxidase (MPO) that catalyses hypochlorous acid (HOCl) production while increasing oxidative stress and inflammation, thereby enhancing ventricular remodelling. Nitroxides inhibit MPO-mediated HOCl production, potentially ameliorating neutrophil-mediated damage. Aim: Assess the cardioprotective ability of nitroxide 4-methoxyTEMPO (4MetT) within the setting of AMI. Methods: Male Wistar rats were separated into 3 groups: SHAM, AMI/R, and AMI/R + 4MetT (15 mg/kg at surgery via oral gavage) and subjected to left descending coronary artery ligation for 30 min to generate an AMI, followed by reperfusion. One cohort of rats were sacrificed at 24 h post-reperfusion and another 28 days post-surgery (with 4MetT (15 mg/kg) administration twice daily). Results: 3-chlorotyrosine, a HOCl-specific damage marker, decreased within the heart of animals in the AMI/R + 4-MetT group 24 h post-AMI, indicating the drug inhibited MPO activity; however, there was no evident difference in either infarct size or myocardial scar size between the groups. Concurrently, MPO, NfκB, TNFα, and the oxidation marker malondialdehyde increased within the hearts, with 4-MetT only demonstrating a trend in decreasing MPO and TNF levels. Notably, 4MetT provided a significant improvement in cardiac function 28 days post-AMI, as assessed by echocardiography, indicating potential for 4-MetT as a treatment option, although the precise mechanism of action of the compound remains unclear. Full article

(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)

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23 pages, 1656 KiB

Open AccessArticle

4,4′-Diaminodiphenyl Sulfone (DDS) as an Inflammasome Competitor

by Jong-hoon Lee, Ha Kyeu An, Mun-Gi Sohn, Paul Kivela and Sangsuk Oh

Int. J. Mol. Sci. 2020, 21(17), 5953; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21175953 - 19 Aug 2020

Cited by 17 | Viewed by 7529

Abstract

The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding [...] Read more.

The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1β, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer’s disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4′-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen’s disease, also diagnosed as Alzheimer’s disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg⁶⁷⁷Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson’s disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor. Full article

(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)

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20 pages, 1658 KiB

Open AccessArticle

Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

by Madeleine Goeritzer, Eva Bernhart, Ioanna Plastira, Helga Reicher, Christina Leopold, Thomas O. Eichmann, Gerald Rechberger, Corina T. Madreiter-Sokolowski, Jürgen Prasch, Philipp Eller, Wolfgang F. Graier, Dagmar Kratky, Ernst Malle and Wolfgang Sattler

Int. J. Mol. Sci. 2020, 21(3), 1143; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031143 - 09 Feb 2020

Cited by 12 | Viewed by 3606

Abstract

During inflammation, activated leukocytes release cytotoxic mediators that compromise blood–brain barrier (BBB) function. Under inflammatory conditions, myeloperoxidase (MPO) is critically involved in inflicting BBB damage. We used genetic and pharmacological approaches to investigate whether MPO induces aberrant lipid homeostasis at the BBB in [...] Read more.

During inflammation, activated leukocytes release cytotoxic mediators that compromise blood–brain barrier (BBB) function. Under inflammatory conditions, myeloperoxidase (MPO) is critically involved in inflicting BBB damage. We used genetic and pharmacological approaches to investigate whether MPO induces aberrant lipid homeostasis at the BBB in a murine endotoxemia model. To corroborate findings in a human system we studied the impact of sera from sepsis and non-sepsis patients on brain endothelial cells (hCMEC/D3). In response to endotoxin, the fatty acid, ceramide, and sphingomyelin content of isolated mouse brain capillaries dropped and barrier dysfunction occurred. In mice, genetic deficiency or pharmacological inhibition of MPO abolished these alterations. Studies in metabolic cages revealed increased physical activity and less pronounced sickness behavior of MPO^−/− compared to wild-type mice in response to sepsis. In hCMEC/D3 cells, exogenous tumor necrosis factor α (TNFα) potently regulated gene expression of pro-inflammatory cytokines and a set of genes involved in sphingolipid (SL) homeostasis. Notably, treatment of hCMEC/D3 cells with sera from septic patients reduced cellular ceramide concentrations and induced barrier and mitochondrial dysfunction. In summary, our in vivo and in vitro data revealed that inflammatory mediators including MPO, TNFα induce dysfunctional SL homeostasis in brain endothelial cells. Genetic and pharmacological inhibition of MPO attenuated endotoxin-induced alterations in SL homeostasis in vivo, highlighting the potential role of MPO as drug target to treat inflammation-induced brain dysfunction. Full article

(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)

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Review

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28 pages, 1106 KiB

Open AccessReview

The Dual Role of Myeloperoxidase in Immune Response

by Jürgen Arnhold

Int. J. Mol. Sci. 2020, 21(21), 8057; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218057 - 29 Oct 2020

Cited by 61 | Viewed by 6907

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)

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22 pages, 707 KiB

Open AccessReview

The Role of Inflammation and Myeloperoxidase-Related Oxidative Stress in the Pathogenesis of Genetically Triggered Thoracic Aortic Aneurysms

by Cassandra Malecki, Brett D. Hambly, Richmond W. Jeremy and Elizabeth N. Robertson

Int. J. Mol. Sci. 2020, 21(20), 7678; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207678 - 16 Oct 2020

Cited by 33 | Viewed by 3765

Abstract

Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with [...] Read more.

Genetically triggered thoracic aortic aneurysms (TAAs) are usually considered to exhibit minimal levels of inflammation. However, emerging data demonstrate that specific features of an inflammatory response can be observed in TAA, and that the extent of the inflammatory response can be correlated with the severity, in both mouse models and in human studies. Myeloperoxidase (MPO) is a key mediator of the inflammatory response, via production of specific oxidative species, e.g., the hypohalous acids. Specific tissue modifications, mediated by hypohalous acids, have been documented in multiple cardiovascular pathologies, including atherosclerosis associated with coronary artery disease, abdominal aortic, and cerebral aneurysms. Similarly, data are now emerging that show the capacity of MPO-derived oxidative species to regulate mechanisms important in TAA pathogenesis, including alterations in extracellular matrix homeostasis, activation of matrix metalloproteinases, induction of endothelial dysfunction and vascular smooth muscle cell phenotypic switching, and activation of ERK1/2 signaling. The weight of evidence supports a role for inflammation in exacerbating the severity of TAA progression, expanding our understanding of the pathogenesis of TAA, identifying potential biomarkers for early detection of TAA, monitoring severity and progression, and for defining potential novel therapeutic targets. Full article

(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)

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19 pages, 1982 KiB

Open AccessReview

The Role of Thiocyanate in Modulating Myeloperoxidase Activity during Disease

by Patrick T. San Gabriel, Yuyang Liu, Angie L. Schroder, Hans Zoellner and Belal Chami

Int. J. Mol. Sci. 2020, 21(17), 6450; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176450 - 03 Sep 2020

Cited by 9 | Viewed by 5611

Abstract

Thiocyanate (SCN⁻) is a pseudohalide anion omnipresent across mammals and is particularly concentrated in secretions within the oral cavity, digestive tract and airway. Thiocyanate can outcompete chlorine anions and other halides (F⁻, Br⁻, I⁻) as [...] Read more.

Thiocyanate (SCN⁻) is a pseudohalide anion omnipresent across mammals and is particularly concentrated in secretions within the oral cavity, digestive tract and airway. Thiocyanate can outcompete chlorine anions and other halides (F⁻, Br⁻, I⁻) as substrates for myeloperoxidase by undergoing two-electron oxidation with hydrogen peroxide. This forms their respective hypohalous acids (HOX where X⁻ = halides) and in the case of thiocyanate, hypothiocyanous acid (HOSCN), which is also a bactericidal oxidative species involved in the regulation of commensal and pathogenic microflora. Disease may dysregulate redox processes and cause imbalances in the oxidative profile, where typically favoured oxidative species, such as hypochlorous acid (HOCl), result in an overabundance of chlorinated protein residues. As such, the pharmacological capacity of thiocyanate has been recently investigated for its ability to modulate myeloperoxidase activity for HOSCN, a less potent species relative to HOCl, although outcomes vary significantly across different disease models. To date, most studies have focused on therapeutic effects in respiratory and cardiovascular animal models. However, we note other conditions such as rheumatic arthritis where SCN⁻ administration may worsen patient outcomes. Here, we discuss the pathophysiological role of SCN⁻ in diseases where MPO is implicated. Full article

(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)

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