Abstract
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.
Highlights
The neurovascular unit separates most regions of the brain from the peripheral circulation to maintain the specialized central nervous system (CNS) micromilieu
We investigated the role of inflammatory mediators (TNFα and serum obtained from sepsis patients) on human brain endothelial cell function
The present study provides evidence that endotoxemia affects FA, Cer, and SM homeostasis in isolated mouse brain microvessels (Figure 1)
Summary
The neurovascular unit separates most regions of the brain from the peripheral circulation to maintain the specialized central nervous system (CNS) micromilieu. Brain microvascular endothelial cells (BMVEC) form the morphological basis of the blood–brain barrier (BBB) by formation of tight junction and adherens junction complexes [1]. These junctional complexes inhibit paracellular leakage, maintain CNS homeostasis via polarized expression of transporter systems, and protect most regions of the brain from injuries. The lipid composition of BMVEC plays a pivotal role in barrier function by establishing a unique environment that inhibits caveolae vesicle formation to suppress transcytosis and ensure BBB integrity [3,4]. Disruptive BBB dysfunction in a murine lipopolysaccharide (LPS)-induced endotoxemia model is accompanied by alterations of the S1P rheostat in brain capillaries and dysregulation of SL homeostasis in serum and brain [11]
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