Myeloperoxidase deficiency enhances zymosan phagocytosis associated with up-regulation of surface expression of CD11b in mouse neutrophils

Fujimoto, Kenta; Motowaki, T; Tamura, N.; Aratani, Yasuaki

doi:10.1080/10715762.2016.1244821

Cited by 8 publications

(7 citation statements)

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“…Free MPO by binding to CD11b/CD18 has also been shown to induce neutrophil activation in an autocrine fashion promoting MAPK and NFkB signaling, ROS production and degranulation (12). Furthermore, MPO KO PMNs were suggested to better phagocyte zymosan particles due to slightly elevated levels of CD11b and the resulting induction of FAK/ ERK signaling (13). However, by doing careful examination of CD11b expression, which included BM-PMNs, circulating blood PMNs with and without stimulation, as well as following adoptive competitive transfer of WT and MPO KO PMNs into inflamed recipient circulation we found no significant differences in CD11b expression.…”

Section: Discussionmentioning

confidence: 99%

“…However, MPO paracrine modulation of PMN activity particularly stands out. 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%

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Released Myeloperoxidase Attenuates Neutrophil Migration and Accumulation in Inflamed Tissue

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Released Myeloperoxidase Attenuates Neutrophil Migration and Accumulation in Inflamed Tissue

et al. 2021

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“…MPO deficiency also reportedly had enhanced phagocytic capability through the absence of ERK1/2 signalling [ 62 ]. Lung neutrophil influx induced by LPS in mice was attenuated in MPO knockout mice [ 63 ].…”

Section: Mpo: It's In (Most Of) Our Genesmentioning

confidence: 99%

The many roles of myeloperoxidase: From inflammation and immunity to biomarkers, drug metabolism and drug discovery

Siraki

2021

Redox Biology

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This review provides a practical guide to myeloperoxidase (MPO) and presents to the reader the diversity of its presence in biology. The review provides a historical background, from peroxidase activity to the discovery of MPO, to its role in disease and drug development. MPO is discussed in terms of its necessity, as specific individuals lack MPO expression. An underlying theme presented throughout brings up the question of the benefit and burden of MPO activity. Enzyme structure is discussed, including accurate masses and glycosylation sites. The catalytic cycle of MPO and its corresponding pathways are presented, with a discussion of the importance of the redox couples of the different states of MPO. Cell lines expressing MPO are discussed and practically summarized for the reader, and locations of MPO (primary and secondary) are provided. Useful methods of MPO detection are discussed, and how these can be used for studying disease processes are implied through the presentation of MPO as a biomarker. The presence of MPO in neutrophil extracellular traps is presented, and the activators of the former are provided. Lastly, the transition from drug metabolism to a target for drug development is where the review concludes.

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“…Furthermore, neutrophils treated with stimuli are rich in MPO-DNA complexes ( 38 ) and, in turn, MPO can regulate the function and immune response of neutrophils. Recent research has shown that MPO can affect the degranulation of neutrophils and improve their phagocytosis ( 39 ), and it can also “break” the migration of neutrophils and prevent their accumulation ( 15 ). The relationship between MPO in CRC and preoperative neutrophil counts is yet to be reported.…”

Section: Discussionmentioning

confidence: 99%

Increased MPO in Colorectal Cancer Is Associated With High Peripheral Neutrophil Counts and a Poor Prognosis: A TCGA With Propensity Score-Matched Analysis

Weng

Yue

et al. 2022

Front. Oncol.

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BackgroundMyeloperoxidase (MPO) has been demonstrated to be a local mediator of inflammation in tissue damage in various inflammatory diseases. Given its controversial effect on colorectal cancer (CRC), there has been growing interest in investigating the role of this enzyme in CRC. The mechanism underlying MPO activity and CRC progression requires further clarification.MethodsThe expression and function of MPO in CRC were evaluated using TCGA analysis. TCGA, TIMER, and Human Cell Landscape analyses were used to analyze the correlation between MPO expression and neutrophil infiltration in CRC. Spearman’s bivariate correlation analysis was used to verify the correlation between MPO levels in CRC and the peripheral neutrophil count. In the clinical analysis, 8,121 patients who underwent elective surgery for CRC were enrolled in this retrospective cohort study from January 2008 to December 2014. Propensity score matching was used to address the differences in baseline characteristics. The Kaplan–Meier method and Cox regression analysis were used to identify independent prognostic factors in patients with CRC.ResultsMPO was upregulated in CRC tissues, which is related to malignant progression and worse survival in CRC patients from TCGA analysis. MPO was significantly correlated with the infiltration level of neutrophils in CRC in TCGA, TIMER, and Human Cell Landscape analyses. MPO was positively correlated with the peripheral neutrophil count. Data of the 8,121 patients who underwent CRC surgery were available for analysis. After propensity score matching, 3,358 patients were included in each group. Kaplan–Meier survival curves showed that high preoperative neutrophil levels were associated with decreased overall survival (OS; P < 0.001) and disease-free survival (DFS; P = 0.015). The preoperative neutrophil count was an independent risk factor for OS (hazard ratio [HR], 1.157; 95% confidence interval [CI], 1.055–1.268; P = 0.002) and DFS (HR, 1.118; 95% CI, 1.009–1.238; P = 0.033).ConclusionsOur research indicates that increased MPO levels in CRC are significantly correlated with high preoperative neutrophil counts, and both serve as prognostic indicators for worse survival in CRC patients. Our study suggests that neutrophils may be key players in the mechanism linking MPO levels with poor CRC outcomes.

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Myeloperoxidase deficiency enhances zymosan phagocytosis associated with up-regulation of surface expression of CD11b in mouse neutrophils

Cited by 8 publications

References 57 publications

Released Myeloperoxidase Attenuates Neutrophil Migration and Accumulation in Inflamed Tissue

Released Myeloperoxidase Attenuates Neutrophil Migration and Accumulation in Inflamed Tissue

The many roles of myeloperoxidase: From inflammation and immunity to biomarkers, drug metabolism and drug discovery

Increased MPO in Colorectal Cancer Is Associated With High Peripheral Neutrophil Counts and a Poor Prognosis: A TCGA With Propensity Score-Matched Analysis

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