Released Myeloperoxidase Attenuates Neutrophil Migration and Accumulation in Inflamed Tissue

Abstract

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.

Alleviation effects of grape seed proanthocyanidin extract on inflammation and oxidative stress in a d-galactose-induced aging mouse model by modulating the gut microbiota

“…21 In addition, the MPO activity served as a reliable marker of the neutrophil activation and high levels of MPO indicate increased inflammation. 22 The present study indicated that the GSPE treatment could suppress the alterations of the increased MPO activities, the increased MDA contents, and the reduced GSH-Px activities, consistent with the research results of the previous studies, 23,24 and the antioxidant capacity of high-dose GSPE was higher than that of low-dose GSPE. Therefore, the findings summarized above established the antioxidant potential capacity of GSPE.…”

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

“…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.…”

“…Given the controversial effect of MPO on CRC, there has been growing interest in investigating the role of this enzyme in CRC. MPO is the most abundant protein expressed by neutrophils and it may also have the greatest potential to damage living cells ( 15 ). In autoimmune diseases, MPO exists only in the cytoplasm of the neutrophils ( 16 ).…”

The effect of Hippophae rhamnoides L. extract on acrylamideinduced brain injury in rats

“…In the literature, there is information that MPO is held responsible in the pathogenesis of many inflammatory diseases, including cardiovascular, kidney, lung, rheumatoid arthritis, skin inflammation and neuronal 23 . The damaging effect of MPO on tissue is enhanced by the formation of hypochlorous acid from hydrogen peroxide and chloride ions 24 . The inhibition of MPO activity by acrylamide by HRE may be due to its inhibition of PNL leakage (infiltration) into the damaged area.…”