Functional Inactivation and Structural Disruption of Human α2-Macroglobulin by Neutrophils and Eosinophils

Reddy, Vidyavathi; Pizzo, Salvatore V.; Weiss, Stephen J.

doi:10.1016/s0021-9258(18)80072-2

Cited by 43 publications

(2 citation statements)

References 56 publications

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“…Nevertheless, we have identified a unique mechanism of R 2 M inactivation in this study that can explain the decrease in R 2 M proteinase inhibitory activity in RA synovial fluid. Earlier studies of R 2 M oxidation by us and others have hypothesized, without direct evidence, that intersubunit crosslinking and tetramer to dimer fragmentation may be responsible for R 2 M inactivation because these modifications are expected to alter the ability of R 2 M to entrap proteinases (25,30,31). We found, in this study, evidence that strongly opposes this hypothesis.…”

Section: Discussioncontrasting

confidence: 44%

Mechanism of Hypochlorite-Mediated Inactivation of Proteinase Inhibition by α₂-Macroglobulin

Pizzo

1999

Biochemistry

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The proteinase-proteinase inhibitor balance plays an important role in mediating inflammation-associated tissue destruction. alpha 2-Macroglobulin (alpha 2M) is a high-affinity, broad-spectrum proteinase inhibitor found abundantly in plasma and interstitial fluids. Increased levels of alpha 2M and proteinase-alpha 2M complexes can be demonstrated in patients with sepsis, emphysema, peridontitis, rheumatoid arthritis, and other inflammatory diseases. Despite these increased levels, proteolysis remains a significant problem. We hypothesized that a mechanism for inactivating alpha 2M-mediated proteinase inhibition must exist and recently demonstrated that alpha 2M isolated from human rheumatoid arthritis synovial fluid is oxidized and has decreased functional activity. The oxidant responsible for alpha 2M inactivation and the mechanism of such destruction were not studied. We now report that while hypochlorite and hydroxyl radical both modify amino acid residues on alpha 2M, only hypochlorite can abolish the ability of alpha 2M to inhibit proteinases. Hydrogen peroxide, on the other hand, has no effect on alpha 2M structure or function. Protein unfolding with increased susceptibility to proteolytic cleavage appears to be involved in alpha 2M inactivation by oxidation. The in vivo relevance of this mechanism is supported by the presence of multiple cleavage fragments of alpha 2M in synovial fluid from patients with rheumatoid arthritis, where significant tissue destruction occurs, but not in patients with osteoarthritis. These results provide strong evidence that hypochlorite oxidation contributes to enhanced tissue destruction during inflammation by inactivating alpha 2M.

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Section: Discussioncontrasting

confidence: 44%

Mechanism of Hypochlorite-Mediated Inactivation of Proteinase Inhibition by α₂-Macroglobulin

Pizzo

1999

Biochemistry

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“…Therefore, it was suggested that neutrophils inactivate A2M by the release of reactive species such as hypochlorite. Through oxidative modification, ROS affect A2M structural integrity and cause dissociation of A2M tetramers into dimers which do not possess anti-proteolytic activity ( 108 – 111 ) ( Figure 4 ). Finally, certain proteases partially escape regulation by A2M.…”

Section: Effects Of A2m On Leukocytesmentioning

confidence: 99%

Alpha-2-Macroglobulin in Inflammation, Immunity and Infections

2021

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Alpha-2-macroglobulin is an extracellular macromolecule mainly known for its role as a broad-spectrum protease inhibitor. By presenting itself as an optimal substrate for endopeptidases of all catalytic types, alpha-2-macroglobulin lures active proteases into its molecular cage and subsequently ‘flags’ their complex for elimination. In addition to its role as a regulator of extracellular proteolysis, alpha-2-macroglobulin also has other functions such as switching proteolysis towards small substrates, facilitating cell migration and the binding of cytokines, growth factors and damaged extracellular proteins. These functions appear particularly important in the context of immune-cell function. In this review manuscript, we provide an overview of all functions of alpha-2-macroglobulin and place these in the context of inflammation, immunity and infections.

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Half‐Curcumin‐Based Chemiluminescence Probes and Their Applications in Detecting Quasi‐Stable Oxidized Proteins

Yang,

Zhu,

Zhang

et al. 2024

Angewandte Chemie

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Numerous methods have been reported for detecting ROS/RNS in vitro and in vivo; however, detecting methods for the secondary products of the ROS/RNS reactions, particularly quasi‐stable oxidized products, have been much less explored. In this report, we observed that half‐curcumins could generate chemiluminescence. In contrast to other chemiluminescence scaffolds, the distinguishing feature of a half‐curcumin is the formation of a carbanion intermediate of its acetylacetone moiety, opening unique avenues for applications. In this study, we designed a series of half‐curcumins CRANAD‐Xs and found that CRANAD‐164 could be used to detect quasi‐stable oxidized proteins (QSOP) in vivo and in patient serum samples. We illustrated that CRANAD‐164 could be used to monitor the responses of taurine, an amino acid with newly reported anti‐aging capacity, in an inflammatory mouse model. Remarkably, we further demonstrated that the QSOP levels were much higher in the disease serum samples, including Alzheimer’s disease, compared to the samples from healthy controls. Moreover, our results revealed that the sera chemiluminescence intensities were higher in aged healthy controls compared to young healthy subjects, suggesting that CRANAD‐164 can be used to monitor the increase of QSOP during aging.

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Functional Inactivation and Structural Disruption of Human α2-Macroglobulin by Neutrophils and Eosinophils

Cited by 43 publications

References 56 publications

Mechanism of Hypochlorite-Mediated Inactivation of Proteinase Inhibition by α₂-Macroglobulin

Mechanism of Hypochlorite-Mediated Inactivation of Proteinase Inhibition by α₂-Macroglobulin

Alpha-2-Macroglobulin in Inflammation, Immunity and Infections

Half‐Curcumin‐Based Chemiluminescence Probes and Their Applications in Detecting Quasi‐Stable Oxidized Proteins

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Functional Inactivation and Structural Disruption of Human α2-Macroglobulin by Neutrophils and Eosinophils

Cited by 43 publications

References 56 publications

Mechanism of Hypochlorite-Mediated Inactivation of Proteinase Inhibition by α2-Macroglobulin

Mechanism of Hypochlorite-Mediated Inactivation of Proteinase Inhibition by α2-Macroglobulin

Alpha-2-Macroglobulin in Inflammation, Immunity and Infections

Half‐Curcumin‐Based Chemiluminescence Probes and Their Applications in Detecting Quasi‐Stable Oxidized Proteins

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Product

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Mechanism of Hypochlorite-Mediated Inactivation of Proteinase Inhibition by α₂-Macroglobulin

Mechanism of Hypochlorite-Mediated Inactivation of Proteinase Inhibition by α₂-Macroglobulin