Human mast cell neutral proteases generate modified LDL particles with increased proteoglycan binding

Maaninka, Katariina; Nguyen, Su Duy; Mäyränpää, Mikko I.; Plihtari, Riia; Rajamäki, Kristiina; Lindsberg, Perttu J.; Kovanen, Petri T.; Öörni, Katariina

doi:10.1016/j.atherosclerosis.2018.04.016

Cited by 20 publications

(21 citation statements)

References 53 publications

(51 reference statements)

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“…Issues related to specificity likely include the small increases in sAT concentrations occurring with random variations or nonanaphylactic events, and mechanisms of anaphylaxis that do not involve MC degranulation . Indeed, MC activation has been reported in atherosclerosis‐related cardiovascular events, coagulation abnormalities, and response to infectious agents . In line with previous cohorts, our results confirm that the consensus algorithm sAT >([1.2 × sBT] + 2) μg/L is a good compromise between empirical thresholds such as >(1.35 × sBT), which privileged sensitivity as high as 0.91 in previous literature and 0.81 in our study, or (sBT + 3) μg/L, which resulted in sensitivity values as low as 0.63 in the literature and 0.72 in our hands.…”

Section: Discussionsupporting

confidence: 84%

Paired acute‐baseline serum tryptase levels in perioperative anaphylaxis: An observational study

Vitte

Amadei

Gouitaa

et al. 2019

Allergy

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Background: Anaphylaxis is recognized mainly through clinical criteria, which may lack specificity or relevance in the perioperative setting. The transient increase in serum tryptase has been proposed since 1989 as a diagnostic tool. Sampling for well-defined acute and baseline determinations has been recommended. We assessed the performance of four proposed algorithms with tightly controlled time frames for tryptase sampling, their robustness with inadequate sampling times, and the possible use of mature tryptase determination. Methods:A retrospective study was performed on 102 adult patients from the Aix-Marseille University Hospitals who had experienced a perioperative hypersensitivity reaction clinically suggesting anaphylaxis. EAACI and ICON criteria were used to diagnose anaphylaxis. Mature and total serum tryptase levels were measured.Results: Based on EAACI guidelines, clinical diagnostic criteria for anaphylaxis were found in 76 patients and lacking in 26. The most effective algorithm was the international consensus recommendation of 2012 that acute total tryptase levels should be greater than ([1.2×baseline tryptase] + 2] μg/L to be considered a clinically significant rise. In our cohort, this algorithm achieved 94% positive predictive value (PPV), 53% negative predictive value (NPV), 75% sensitivity, 86% specificity, and a Youden's index value of 0.61. A detectable acute mature tryptase level showed lower sensitivity, particularly in patients with acute total tryptase levels lower than 16 μg/ L. Acute tryptase levels varied as a function of the clinical severity of anaphylaxis. Conclusion:Total tryptase levels in serum discriminated between nonanaphylactic and anaphylactic events in a perioperative setting when acute and baseline levels were collected and analyzed by the consensus algorithm. K E Y W O R D Sacute tryptase, anaphylaxis, anesthesia, baseline tryptase, hypersensitivity reaction, mast cell, mature tryptase, perioperative anaphylaxis, positive predictive value Abbreviations: Ig, immunoglobulin; IQR, interquartile range; MC, mast cell; NMBA, neuromuscular blocking agents; NPV, negative predictive value; PA, perioperative anaphylaxis; PPV, positive predictive value; sAT, serum acute tryptase; sBT, serum baseline tryptase; SHR, systemic hypersensitivity reaction.

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Section: Discussionsupporting

confidence: 84%

Paired acute‐baseline serum tryptase levels in perioperative anaphylaxis: An observational study

Vitte

Amadei

Gouitaa

et al. 2019

Allergy

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“…HuChem-156 is produced by cathepsin G, chymase or kallikrein 7 from huChem-163 [ 1 ]. These proteases are expressed by mast cells, which contribute to liver fibrosis and HCC [ 40 , 41 , 42 ]. Whether huChem-156 is abundant in human liver needs further analysis.…”

Section: Discussionmentioning

confidence: 99%

Chemerin-156 is the Active Isoform in Human Hepatic Stellate Cells

Spirk

Zimny

Neumann

et al. 2020

IJMS

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The chemokine chemerin exists as C-terminally processed isoforms whose biological functions are mostly unknown. A highly active human chemerin variant (huChem-157) was protective in experimental hepatocellular carcinoma (HCC) models. Hepatic stellate cells (HSCs) are central mediators of hepatic fibrogenesis and carcinogenesis and express the chemerin receptors chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1). Here we aimed to analyse the effect of chemerin isoforms on the viability, proliferation and secretome of the human HSC cell line LX-2. Therefore, huChem-157, 156 and 155 were over-expressed in LX-2 cells, which have low endogenous chemerin levels. HuChem-157 produced in LX-2 cells activated CMKLR1 and GPR1, and huChem-156 modestly induced GPR1 signaling. HuChem-155 is an inactive chemerin variant. Chemerin isoforms had no effect on cell viability and proliferation. Cellular expression of the fibrotic proteins galectin-3 and alpha-smooth muscle actin was not regulated by any chemerin isoform. HuChem-156 increased IL-6, IL-8 and galectin-3 in cell media. HuChem-157 was ineffective, and accordingly, did not enhance levels of these proteins in media of primary human hepatic stellate cells when added exogenously. These analyses provide evidence that huChem-156 is the biologic active chemerin variant in hepatic stellate cells and acts as a pro-inflammatory factor.

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“…Cleavage of VE-cadherin mediated by elastase, one of the proteases associated with NETs, abolishes cell–cell contacts and increases cell permeability (64). Recent evidence demonstrated that cathepsin G, which is also a NETs-associating protease, mediates the degradation of apoB in native LDL to cause LDL fusion and enhanced binding of LDL to isolated human aortic proteoglycans and human atherosclerotic lesions ex vivo , thereby contributing to atherogenesis (65, 66). Interestingly, it is presumable that cooperative pathophysiological relevance of proteases on NETs and lipoproteins causes the progression of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Cooperative Action of Oxidized Low-Density Lipoproteins and Neutrophils on Endothelial Inflammatory Responses Through Neutrophil Extracellular Trap Formation

et al. 2019

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The function of oxidatively modified low-density lipoprotein (oxLDL) in the progression of cardiovascular diseases has been extensively investigated and well-characterized with regards to the activation of multiple cellular responses in macrophages and endothelial cells. Although accumulated evidence has revealed the presence of neutrophils in vascular lesions, the effect of oxLDL on neutrophil function has not been properly investigated. In the present decade, neutrophil extracellular traps (NETs) gained immense attention not only as a primary response against pathogenic bacteria but also due to their pathological roles in tissue damage in various diseases, such as atherosclerosis and thrombosis. In this study, we investigated if oxLDL affects NET formation and if it is a risk factor for inflammatory reactions in endothelial cells. HL-60-derived neutrophils were stimulated with phorbol 12-myristate 13-acetate (PMA) for 30 min to induce NET formation, followed by incubation with 20 μg/mL native or oxidized LDL for additional 2 h. Culture media of the stimulated cells containing released NETs components were collected to evaluate NET formation by fluorometric quantitation of released DNA and detection of myeloperoxidase (MPO) by western blot analysis. NET formation of HL-60-derived neutrophils induced by PMA was significantly enhanced by additional incubation with oxLDL but not with native LDL. Treatment of HL-60-derived neutrophils with oxLDL alone in the absence of PMA did not induce NET formation. Furthermore, the culture media of HL-60-derived neutrophils after NET formation were then transferred to human aortic endothelial cell (HAECs) culture. Treatment of HAECs with the culture media containing NETs formed by HL-60-derived neutrophils increased the expression of metalloproteinase-1 protein in HAECs when HL-60-derived neutrophils were incubated with native LDL, and the expression was accelerated in the case of oxLDL. In addition, the culture media from NETs formed by HL-60-derived neutrophils caused the elongation of HAECs, which was immensely enhanced by coincubation with native LDL or oxLDL. These data suggest that oxLDL may act synergistically with neutrophils to form NETs and promote vascular endothelial inflammation.

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Human mast cell neutral proteases generate modified LDL particles with increased proteoglycan binding

Abstract: The present study suggests that cathepsin G in human atherosclerotic lesions is largely derived from MCs and that activated MCs may contribute to atherogenesis by enhancing LDL retention.

Cited by 20 publications

References 53 publications

Paired acute‐baseline serum tryptase levels in perioperative anaphylaxis: An observational study

Paired acute‐baseline serum tryptase levels in perioperative anaphylaxis: An observational study

Chemerin-156 is the Active Isoform in Human Hepatic Stellate Cells

Cooperative Action of Oxidized Low-Density Lipoproteins and Neutrophils on Endothelial Inflammatory Responses Through Neutrophil Extracellular Trap Formation

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