Concept: Myeloperoxidase deficiency
Abstract Myeloperoxidase (MPO), a major constituent of neutrophils, catalyzes the production of hypochlorous acid (HOCl) from hydrogen peroxide (H(2)O(2)) and chloride anion. We have previously reported that MPO-deficient (MPO(-/-)) neutrophils produce greater amount of macrophage inflammatory protein-2 (MIP-2) in vitro than do wild-type when stimulated with zymosan. In this study, we investigated the molecular mechanisms governing the up-regulation of MIP-2 production in the mutant neutrophils. Interestingly, we found that zymosan-induced production of MIP-2 was blocked by pre-treatment with U0126, an inhibitor of mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK), and with BAY11-7082, an inhibitor of nuclear factor (NF)-κB. Western blot analysis indicated that U0126 also inhibited the phosphorylation of p65 subunit of NF-κB (p65), indicating that MIP-2 was produced via the ERK/NF-κB pathway. Intriguingly, we found that ERK1/2, p65, and alpha subunit of inhibitor of κB (IκBα) in the MPO(-/-) neutrophils were phosphorylated more strongly than in the wild-type when stimulated with zymosan. Exogenous H(2)O(2) treatment in addition to zymosan stimulation enhanced the phosphorylation of ERK1/2 without affecting the zymosan-induced MIP-2 production. In contrast, exogenous HOCl inhibited the production of MIP-2 as well as IκBα phosphorylation without affecting ERK activity. The zymosan-induced production of MIP-2 in the wild-type neutrophils was enhanced by pre-treatment of the MPO inhibitor 4-Aminobenzoic acid hydrazide. Collectively, these results strongly suggest that both lack of HOCl and accumulation of H(2)O(2 )due to MPO deficiency contribute to the up-regulation of MIP-2 production in mouse neutrophils stimulated with zymosan.
The pathogenesis of acquired myeloperoxidase (MPO) deficiency, a rare phenomenon observed in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), is unknown. MPO is a glycoprotein chaperoned by Calreticulin (CALR) in the endoplasmic reticulum. Mutations inCALRare frequently found in patients with myelofibrosis (MF) and essential thrombocythemia (ET) with nonmutatedJanuskinase 2(JAK2). We hypothesized that acquired MPO deficiency in MPN could be associated with the presence ofCALRmutations. A cohort of 317 MPN patients (142 polycythemia vera (PV), 94 ET and 81 MF) was screened for MPO deficiency. MPO deficiency was observed in 6/81 MF patients (7.4%), but not in PV or ET patients. Susceptibility to infections had been documented in 2/6 (33%) MPO deficient patients. Five out of six patients with MPO deficiency carried a homozygousCALRmutation and were also deficient in eosinophilic peroxidase (EPX). In contrast, one MF patient with aJAK2-V617F mutation and MPO deficiency carried two previously reportedMPOmutations and showed normal EPX activity. Patients with homozygousCALRmutations had reduced MPO protein, but normalMPOmRNA levels supporting a post-transcriptional defect in MPO production. Finally, we demonstrate in vitro that in the absence of CALR immature MPO protein precursors are degraded in the proteasome. Therefore, four decades after the first description of acquired MPO deficiency in MPN we provide the molecular correlate associated with this phenomenon and evidence thatCALRmutations can affect the biosynthesis of glycoproteins.
Abstract Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/ macrophages. Beside its well defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wildtype mice. Methods: CKD was induced by 5/6 nephrectomy. Mice were followed for 10 weeks to evaluate the impact of MPO deficiency on renal morbidity. Results: Renal ablation induced CKD in wildtype mice with increased plasma levels of MPO compared to controls. No difference was found between MPO deficient and wildtype mice regarding albuminuria one week after renal ablation indicating similar acute responses to renal ablation. Over the next 10 weeks, however, MPO deficient mice developed significantly less albuminuria and glomerular injury than wildtype mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes PAI-1, collagen type III, and IV as well as MMP-2 and MMP-9. MPO deficient mice also developed less renal inflammation after renal ablation as indicated by a lower infiltration of CD3 positive T cells, F4/80 positive monocytes/macrophages, and GR-1 positive neutrophils compared to wildtype mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO deficient mice was impaired compared to wildtype mice. No significant differences were observed for mortality and blood pressure after renal ablation. Conclusion: These results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.
Myeloperoxidase deficiency in mice exacerbates lung inflammation induced by nonviable Candida albicans
- Inflammation research : official journal of the European Histamine Research Society ... [et al.]
- Published over 4 years ago
This study aimed to evaluate the effect of myeloperoxidase (MPO) deficiency on lung inflammation induced by nonviable Candida albicans (nCA).