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Myeloperoxidase Negatively Regulates Neutrophil-Endothelial Cell Interactions by Impairing ?M?2 Integrin Function in Sterile Inflammation.

ABSTRACT: Interactions of neutrophils with endothelial cells (ECs) and platelets contribute to tissue damage and vascular occlusion under sterile inflammatory conditions. However, the molecular mechanisms regulating the cell-cell interactions remain poorly understood. Previous studies suggest that reactive oxygen species, such as hydrogen peroxide (H2O2), produced from NADPH oxidase 2 play a critical role in platelet-neutrophil interactions by regulating the function of neutrophil ?M?2 integrin during sterile inflammation. In this study, we further demonstrate a crucial role for myeloperoxidase (MPO) in regulating the adhesive function of neutrophils through ?M?2 integrin. Using real-time fluorescence intravital microscopy and in vitro assays, we showed that loss of MPO promoted neutrophil-EC interactions and neutrophil emigration but did not affect neutrophil-platelet interactions under inflammatory conditions. Using genetic and pharmacologic approaches, we found that following agonist stimulation, MPO knockout (KO) neutrophils exhibited a significant increase in extracellular H2O2 and surface level of ?M?2 integrin and that these effects were dependent on MPO activity. Our in vivo studies using an ischemia/reperfusion-induced hepatic inflammation model revealed that compared to wild-type mice, neutrophils from MPO KO mice-displayed a pro-migratory phenotype while ameliorating tissue damage. These results suggest that MPO plays a negative role in the adhesive and migratory function of neutrophils by impairing ?M?2 integrin function under sterile inflammatory conditions.

SUBMITTER: Tseng A

PROVIDER: S-EPMC5946029 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Myeloperoxidase Negatively Regulates Neutrophil-Endothelial Cell Interactions by Impairing αMβ2 Integrin Function in Sterile Inflammation.

Tseng Alan A Kim Kyungho K Li Jing J Cho Jaehyung J

Frontiers in medicine 20180504

Interactions of neutrophils with endothelial cells (ECs) and platelets contribute to tissue damage and vascular occlusion under sterile inflammatory conditions. However, the molecular mechanisms regulating the cell-cell interactions remain poorly understood. Previous studies suggest that reactive oxygen species, such as hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), produced from NADPH oxidase 2 play a critical role in platelet-neutrophil interactions by regulating the function of neutrophil αM ...[more]

PMID: 29780806

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Project description:BackgroundMyeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN.MethodsWe evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis.ResultsAll biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses.ConclusionsMyeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN.

Dataset Information

Myeloperoxidase Negatively Regulates Neutrophil-Endothelial Cell Interactions by Impairing ?M?2 Integrin Function in Sterile Inflammation.

Publications

Myeloperoxidase Negatively Regulates Neutrophil-Endothelial Cell Interactions by Impairing αMβ2 Integrin Function in Sterile Inflammation.

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