Non-Canonical Functions of Myeloperoxidase in Immune Regulation, Tissue Inflammation and Cancer

Lockhart, J. Scott; Sumagin, Ronen

doi:10.3390/ijms232012250

Cited by 14 publications

(10 citation statements)

References 183 publications

(213 reference statements)

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“…Beyond our work, inhibition of myeloperoxidase has been proposed as a treatment for a number of conditions in which there is compelling evidence that myeloperoxidase and/or its oxidant products are central to disease etiology (extensively reviewed in [ 76 , 77 ]). The oxidative stress and resulting proinflammatory milieu observed in conditions such as atherosclerosis [ 78 ], rheumatoid arthritis [ 79 ], kidney disease [ 80 ], inflammatory bowel disease [ 81 ], and neurodegenerative disorders [ 82 ] have commonly been attributed to the activity or overactivity of myeloperoxidase.…”

Section: Discussionmentioning

confidence: 99%

The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic Update for Idiosyncratic Drug-Induced Agranulocytosis

Sernoskie

Jee

Uetrecht

2023

IJMS

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The risk of idiosyncratic drug-induced agranulocytosis (IDIAG) markedly constrains the use of clozapine, a neuroleptic with unparalleled efficacy. Most clozapine patients experience an early inflammatory response, likely a necessary step in IDIAG onset. However, most patients do not progress to IDIAG, presumably because of the requirement of specific human leukocyte antigen (HLA) haplotypes, T cell receptors, and other unknown factors. We established that clozapine activates inflammasomes and that myeloperoxidase bioactivation of clozapine generates neoantigens, but the connection between these early mechanistic events remained unknown and, thus, was the aim of this work. We found that the myeloperoxidase inhibitor PF-1355 attenuated myeloperoxidase activity in phorbol myristate acetate (PMA)-differentiated THP-1 macrophages, and it also attenuated clozapine-induced release of inflammatory mediators (e.g., IL-1β, CXCL1, and C-reactive protein). In vivo, pretreatment of Sprague Dawley rats with PF-1355 significantly attenuated clozapine-induced increases in neutrophil mobilization from the bone marrow to the blood and spleen, as determined using differential blood counts and flow cytometry. Moreover, the clozapine-triggered release of inflammatory mediators (e.g., IL-1β, calprotectin, CXCL1, and α-1-acid glycoprotein) from the liver, spleen, and bone marrow was dampened by myeloperoxidase inhibition. These data support the working hypothesis that oxidation of clozapine to a reactive metabolite by myeloperoxidase is critical for induction of the inflammatory response to clozapine. Ultimately, a better mechanistic understanding of the early events involved in the immune response to clozapine may elucidate ways to prevent IDIAG, enabling safer, more frequent therapeutic use of this and potentially other highly efficacious drugs.

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Section: Discussionmentioning

confidence: 99%

The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic Update for Idiosyncratic Drug-Induced Agranulocytosis

Sernoskie

Jee

Uetrecht

2023

IJMS

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“…NET release inhibited metastasis and was cytotoxic to melanoma cells in vitro. In contrast, NETs promoted metastasis in breast cancer models, indicating that perhaps the outcome of NET activity is model dependent and perhaps canonical vs. non-canonical MPO function [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

The Effect of Acetylsalicylic Acid, as a Representative Non-Steroidal Anti-Inflammatory Drug, on the Activity of Myeloperoxidase

et al. 2023

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Background: Acetylsalicylic acid (ASA or aspirin) is one of the world’s most widely used non-steroidal anti-inflammatory drug (NSAID). Numerous studies have shown that the long-term use of aspirin may contribute to longer survival among patients with various types of cancer, including ovarian cancer. Aim: The aim of this study was to investigate the effect of ASA on myeloperoxidase (MPO), which is found at an elevated level in women with ovarian cancer, among others. Methods: The influence of different concentrations of ASA on the chlorinating and peroxidase activity of MPO was analysed. The relationship between the concentration of ASA and the degree of inhibition of MPO activity was determined based on the results. Conclusions: Aspirin has a significant effect on MPO activity. The use of 50 mM ASA resulted in the enzyme activity being inhibited by more than 90%.

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“…MPO is one of the most abundantly expressed proteins in neutrophils. Aside from the involvement in the antimicrobial defense system, it contributes to neutrophil longevity, tissue inflammation and cancer [ 55 ]. Cathepsin G is one of the three serine proteases localized in the primary granules of neutrophils.…”

Section: Resultsmentioning

confidence: 99%

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion

et al. 2022

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The invasion and integrin-dependent adhesion of neutrophils to lung tissues and their secretion lead to the development of pneumonia in various pulmonary pathologies, including acute respiratory distress syndrome in coronavirus disease. We studied the effect of ivermectin, a possible therapeutic agent for inflammation and cancer, on integrin-dependent neutrophil adhesion to fibronectin and the concomitant secretion. Ivermectin did not affect the attachment of neutrophils to the substrate and the reactive oxygen species production but sharply inhibited the adhesion-induced release of hydroxylysine and stimulated the release of phenylalanine and cathepsin G. Hydroxylysine is a product of lysyl hydroxylase, which is overexpressed in tumor cells with an increased ability to invade and metastasize. The inhibition of hydroxylysine release by ivermectin, by analogy, may indicate the suppression of neutrophil invasion into tissue. The increase in the release of phenylalanine in our experiments coincided with the secretion of cathepsin G, which indicates the possible role of this enzyme in the cleavage of phenylalanine. What is the substrate in such a reaction is unknown. We demonstrated that exogenously added angiotensin II (1–8) can serve as a substrate for phenylalanine cleavage. Mass spectrometry revealed the formation of angiotensin II (1–7) in the secretion of neutrophils, which attached to fibronectin in the presence of ivermectin and exogenous angiotensin II (1–8), indicating a possible involvement of ivermectin in the inactivation of angiotensin II.

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Non-Canonical Functions of Myeloperoxidase in Immune Regulation, Tissue Inflammation and Cancer

Cited by 14 publications

References 183 publications

The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic Update for Idiosyncratic Drug-Induced Agranulocytosis

The Role of Myeloperoxidase in Clozapine-Induced Inflammation: A Mechanistic Update for Idiosyncratic Drug-Induced Agranulocytosis

The Effect of Acetylsalicylic Acid, as a Representative Non-Steroidal Anti-Inflammatory Drug, on the Activity of Myeloperoxidase

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion

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