Neutrophil activation in response to monomeric myeloperoxidase

Gorudko, Irina V.; Grigorieva, Daria V.; Sokolov, A. V.; Shamova, Ekaterina V.; Kostevich, Valeria A.; Kudryavtsev, I. V.; Syromiatnikova, Elena D.; Vasilyev, V. B.; Черенкевич, С. Н.; Панасенко, О. М.

doi:10.1139/bcb-2017-0290

Cited by 30 publications

(28 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Single-molecule mass photometry, a method capable of quantifying the assembly, binding affinities and kinetics of protein complexes (41)(42)(43) confirmed that nMPO exists as a lowabundance monoprotomer (αβ, 7%) and highabundance diprotomer (ααββ, 93%) with an apparent mono-/diprotomer (αβ/ααββ) K d of ~50 pM, Figure 1G. The biological role(s) of the maturely processed monoprotomeric MPO, which differs from the secreted monoprotomeric proMPO reportedly elevated in blood in cardiovascular disease (44,45), remains unknown.…”

Section: Comprehensive Characterisation Of Neutrophilderived Myelopermentioning

confidence: 89%

Hyper-truncated Asn355- and Asn391-glycans modulate the activity of neutrophil granule myeloperoxidase

Tjondro

Ugonotti

Kawahara

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

Myeloperoxidase (MPO) plays essential roles in neutrophil-mediated immunity via the generation of reactive oxidation products. Complex carbohydrates decorate MPO at discrete sites, but their functional relevance remains elusive. To this end, we have characterised the structure–biosynthesis–activity relationship of neutrophil MPO (nMPO). Mass spectrometry demonstrated that nMPO carries both characteristic under-processed and hyper-truncated glycans. Occlusion of the Asn355/Asn391-glycosylation sites and the Asn323-/Asn483-glycans, located in the MPO dimerisation zone, was found to affect the local glycan processing, thereby providing a molecular basis of the site-specific nMPO glycosylation. Native mass spectrometry, mass photometry and glycopeptide profiling revealed significant molecular complexity of diprotomeric nMPO arising from heterogeneous glycosylation, oxidation, chlorination and polypeptide truncation variants and a previously unreported low-abundance monoprotomer. Longitudinal profiling of maturing, mature, granule-separated and pathogen-stimulated neutrophils demonstrated that nMPO is dynamically expressed during granulopoiesis, unevenly distributed across granules and degranulated upon activation. We also show that proMPO-to-MPO maturation occurs during early/mid-stage granulopoiesis. While similar global MPO glycosylation was observed across conditions, the conserved Asn355-/Asn391-sites displayed elevated glycan hyper-truncation, which correlated with higher enzyme activities of MPO in distinct granule populations. Enzymatic trimming of the Asn355-/Asn391-glycans recapitulated the activity gain and showed that nMPO carrying hyper-truncated glycans at these positions exhibits increased thermal stability, polypeptide accessibility and ceruloplasmin-mediated inhibition potential relative to native nMPO. Finally, molecular modelling revealed that hyper-truncated Asn355-glycans positioned in the MPO-ceruloplasmin interface are critical for uninterrupted inhibition. Here, through an innovative and comprehensive approach, we report novel functional roles of MPO glycans, providing new insight into neutrophil-mediated immunity.

show abstract

Section: Comprehensive Characterisation Of Neutrophilderived Myelopermentioning

confidence: 89%

Hyper-truncated Asn355- and Asn391-glycans modulate the activity of neutrophil granule myeloperoxidase

Tjondro

Ugonotti

Kawahara

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Increased plasma myeloperoxidase levels were detected in patients with acute coronary syndromes or sepsis and were associated with disease severity (41). Dissociation of myeloperoxidase into monomers with diminished biological activities may represent a mechanism to limit neutrophil responses to this protein (97).…”

Section: Extending Neutrophil Lifespan and Suppression Of Apoptosismentioning

confidence: 99%

β2 Integrin Regulation of Neutrophil Functional Plasticity and Fate in the Resolution of Inflammation

2021

View full text Add to dashboard Cite

Neutrophils act as the first line of cellular defense against invading pathogens or tissue injury. Their rapid recruitment into inflamed tissues is critical for the elimination of invading microorganisms and tissue repair, but is also capable of inflicting damage to neighboring tissues. The β2 integrins and Mac-1 (CD11b/CD18, αMβ2 or complement receptor 3) in particular, are best known for mediating neutrophil adhesion and transmigration across the endothelium and phagocytosis of microbes. However, Mac-1 has a broad ligand recognition property that contributes to the functional versatility of the neutrophil population far beyond their antimicrobial function. Accumulating evidence over the past decade has demonstrated roles for Mac-1 ligands in regulating reverse neutrophil transmigration, lifespan, phagocytosis-induced cell death, release of neutrophil extracellular traps and efferocytosis, hence extending the traditional β2 integrin repertoire in shaping innate and adaptive immune responses. Understanding the functions of β2 integrins may partly explain neutrophil heterogeneity and may be instrumental to develop novel therapies specifically targeting Mac-1-mediated pro-resolution actions without compromising immunity. Thus, this review details novel insights on outside-in signaling through β2 integrins and neutrophil functional heterogeneity pertinent to the resolution of inflammation.

show abstract

“…Free MPO has been shown to bind CD11b at the PMN surface and via these interactions, trigger MAPK-and NFkB-dependent ROS production and degranulation by PMNs (12) or improve phagocytosis via the induction of FAK/ERK signaling (13). MPO has also been shown to provide adhesive support for PMNs (14) and modulate both Ca 2+ levels and cytoskeleton organization (15), suggesting its potential role in PMN trafficking.…”

Section: Introductionmentioning

confidence: 99%

Released Myeloperoxidase Attenuates Neutrophil Migration and Accumulation in Inflamed Tissue

et al. 2021

View full text Add to dashboard Cite

Neutrophil (PMN) recruitment to sites of insult is critical for host defense, however excessive PMN activity and tissue accumulation can lead to exacerbated inflammation and injury. Myeloperoxidase (MPO) is a PMN azurophilic granule enzyme, which together with H2O2, forms a powerful antimicrobial system designed to kill ingested bacteria. Intriguingly, in addition to intracellular killing of invading microorganisms and extracellular tissue damage due generation of ROS, soluble MPO has been directly implicated in modulating cellular responses and tissue homeostasis. In the current work, we used several models of inflammation, murine and human PMNs and state-of-the-art intravital microscopy to examine the effect of MPO on PMN migration and tissue accumulation. We found that in the absence of functional MPO (MPO knockout, KO mice) inflammatory PMN tissue accumulation was significantly enhanced. We determined that the elevated numbers of PMNs in MPO knockout mice was not due to enhanced viability, but due to increased migratory ability. Acute PMN migration in models of zymosan-induced peritonitis or ligated intestinal loops induced by intraluminal administration of PMN-chemokine CXCL1 was increased over 2-fold in MPO KO compared to wild type (WT) mice. Using real-time intravital imaging of inflamed mouse cremaster muscle and ex vivo PMN co-culture with inflamed endothelial cells (ECs) we demonstrate that elevated migration of MPO KO mice was due to enhanced adhesive interactions. In contrast, addition of soluble recombinant MPO both in vivo and ex vivo diminished PMN adhesion and migration. Although MPO has been previously suggested to bind CD11b, we found no significant difference in CD11b expression in either resting or activated PMNs and further showed that the MPO binding to the PMN surface is not specific to CD11b. As such, our data identify MPO as a novel regulator of PMN trafficking in inflammation.

show abstract

Neutrophil activation in response to monomeric myeloperoxidase

Cited by 30 publications

References 51 publications

Hyper-truncated Asn355- and Asn391-glycans modulate the activity of neutrophil granule myeloperoxidase

Hyper-truncated Asn355- and Asn391-glycans modulate the activity of neutrophil granule myeloperoxidase

β2 Integrin Regulation of Neutrophil Functional Plasticity and Fate in the Resolution of Inflammation

Released Myeloperoxidase Attenuates Neutrophil Migration and Accumulation in Inflamed Tissue

Contact Info

Product

Resources

About