Alteration of sphingolipid metabolism as a putative mechanism underlying LPS‐induced BBB disruption
Abstract
Septic encephalopathy with confusion and agitation occurs early during sepsis and contributes to the severity of the disease. A decrease in the sphingosine‐1‐phosphate (S1P) blood levels has been shown in patients and in animal models of sepsis. The lipid mediator S1P is known to be involved in endothelial barrier function in a context‐dependent manner. We utilized lipopolysaccharide (LPS)‐injected mice as a model for septic encephalopathy and first performed tracer permeability assays to assess the blood–brain barrier (BBB) breakdown in vivo. At time points corresponding to the BBB breakdown post LPS injection, we aimed to characterize the regulation of the sphingolipid signaling pathway at the BBB during sepsis. We measured sphingolipid concentrations in blood, in mouse brain microvessels (MBMV s), and brain tissue. We also analyzed the expression of S1P receptors, transporters, and metabolizing enzymes in MBMV s and brain tissue. Primary mouse brain microvascular endothelial cells (MBMEC s) were isolated to evaluate the effects of LPS on transendothelial electrical resistance (TEER) as a measure of permeability in vitro. We observed a relevant decrease in S1P levels after LPS injection in all three compartments (blood, MBMV s, brain tissue) that was accompanied by an increased expression of the S1P receptor type 1 and of sphingosine kinase 1 on one hand and of the S1P degrading enzymes lipid phosphate phosphatase 1 (LPP 1) and S1P phosphatase 1 on the other hand, as well as a down‐regulation of sphingosine kinase 2. Application of LPS to a monolayer of primary MBMEC s did not alter TEER, but serum from LPS‐treated mice lead to a breakdown of the barrier compared to serum from vehicle‐treated mice. We observed profound alterations of the sphingolipid metabolism at the BBB after LPS injection that point toward a therapeutic potential of drugs interfering with this pathway as novel approach for the detrimental overwhelming immune response in sepsis. image Read the Editorial Highlight for this article on page 115. Cover Image for this Issue: doi. 10.1111/jnc.14161.
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High plasma levels of endotoxin can increase permeability of the blood-brain barrier, allowing toxic plasma components, including amyloid β and α-synuclein into the brain.
“High plasma levels of endotoxin can increase permeability of the blood-brain barrier, allowing toxic plasma components, including amyloid β and α-synuclein into the brain [49–51].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [49]
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The endotoxin hypothesis of neurodegeneration
Brown, G. C. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1564-7 · Cited by 457 · see citing works
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- Authors
- Vutukuri, R., Brunkhorst, R., Kestner, R., Hansen, L., Bouzas, N. F., Pfeilschifter, J., Devraj, K., & Pfeilschifter, W.
- Affiliations
- Goethe University Frankfurt (DE)
- Pharmazentrum Frankfurt Institute for Clinical Pharmacology Goethe University Frankfurt Germany
- Corresponding author
- Devraj, Kavi
- Pfeilschifter, Waltraud
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2017-12-28
- Volume
- 144
- Issue
- 2
- Pages
- 172-185
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2761536354
- Cited by
- 57
- References
- 55
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 14 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 1
- FWCI
- 1.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- sphingolipid metabolism, sphingosine-1-phosphate, blood-brain barrier disruption, lipopolysaccharide, sepsis-associated encephalopathy, sepsis, brain microvascular endothelial cells, S1P1 receptor, sphingosine kinase 1, sphingosine kinase 2, endothelial barrier function, transendothelial electrical resistance, cerebral microvasculature
- MeSH terms
- Animals, Blood-Brain Barrier, Brain Chemistry, Capillary Permeability, Cell Membrane Permeability, Lipopolysaccharides, Lysophospholipids, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Sphingolipids, Sphingosine, Endothelial Cells, Receptors, Lysosphingolipid, Mice, Microvessels, Primary Cell Culture
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