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Open AccessArticle

Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

1
Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz 8010, Austria
2
BioTechMed-Graz, Graz 8010, Austria
3
Institute of Molecular Biosciences, University of Graz, Graz 8010, Austria
4
Center for Explorative Lipidomics, BioTechMed-Graz, Graz 8010, Austria
5
Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach 8603, Switzerland
6
Department of Internal Medicine, Intensive Care Unit, Medical University of Graz, Graz 8036, Austria
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 1143; https://doi.org/10.3390/ijms21031143
Received: 12 December 2019 / Revised: 27 January 2020 / Accepted: 6 February 2020 / Published: 9 February 2020
(This article belongs to the Special Issue Role for the Enzyme Myeloperoxidase to Elicit Pathologies)
During inflammation, activated leukocytes release cytotoxic mediators that compromise blood–brain barrier (BBB) function. Under inflammatory conditions, myeloperoxidase (MPO) is critically involved in inflicting BBB damage. We used genetic and pharmacological approaches to investigate whether MPO induces aberrant lipid homeostasis at the BBB in a murine endotoxemia model. To corroborate findings in a human system we studied the impact of sera from sepsis and non-sepsis patients on brain endothelial cells (hCMEC/D3). In response to endotoxin, the fatty acid, ceramide, and sphingomyelin content of isolated mouse brain capillaries dropped and barrier dysfunction occurred. In mice, genetic deficiency or pharmacological inhibition of MPO abolished these alterations. Studies in metabolic cages revealed increased physical activity and less pronounced sickness behavior of MPO−/− compared to wild-type mice in response to sepsis. In hCMEC/D3 cells, exogenous tumor necrosis factor α (TNFα) potently regulated gene expression of pro-inflammatory cytokines and a set of genes involved in sphingolipid (SL) homeostasis. Notably, treatment of hCMEC/D3 cells with sera from septic patients reduced cellular ceramide concentrations and induced barrier and mitochondrial dysfunction. In summary, our in vivo and in vitro data revealed that inflammatory mediators including MPO, TNFα induce dysfunctional SL homeostasis in brain endothelial cells. Genetic and pharmacological inhibition of MPO attenuated endotoxin-induced alterations in SL homeostasis in vivo, highlighting the potential role of MPO as drug target to treat inflammation-induced brain dysfunction. View Full-Text
Keywords: blood–brain barrier; calorimetry; ceramides; cytokines; fatty acid; mitochondrial function; myeloperoxidase; sphingomyelins blood–brain barrier; calorimetry; ceramides; cytokines; fatty acid; mitochondrial function; myeloperoxidase; sphingomyelins
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Goeritzer, M.; Bernhart, E.; Plastira, I.; Reicher, H.; Leopold, C.; Eichmann, T.O.; Rechberger, G.; Madreiter-Sokolowski, C.T.; Prasch, J.; Eller, P.; Graier, W.F.; Kratky, D.; Malle, E.; Sattler, W. Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro. Int. J. Mol. Sci. 2020, 21, 1143.

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