Cargando…
HDL and LDL have distinct, opposing effects on LPS-induced brain inflammation
Endotoxemia and sepsis induce neuroinflammation and increase the risk of neurodegenerative disorders although the mechanism by which peripheral infection leads to brain inflammation is not well understood. While circulating serum lipoproteins are known immunometabolites with the potential to modulat...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124044/ https://www.ncbi.nlm.nih.gov/pubmed/37095493 http://dx.doi.org/10.1186/s12944-023-01817-z |
_version_ | 1785029771785142272 |
---|---|
author | Radford-Smith, Daniel E. Yates, Abi G. Rizvi, Laila Anthony, Daniel C. Probert, Fay |
author_facet | Radford-Smith, Daniel E. Yates, Abi G. Rizvi, Laila Anthony, Daniel C. Probert, Fay |
author_sort | Radford-Smith, Daniel E. |
collection | PubMed |
description | Endotoxemia and sepsis induce neuroinflammation and increase the risk of neurodegenerative disorders although the mechanism by which peripheral infection leads to brain inflammation is not well understood. While circulating serum lipoproteins are known immunometabolites with the potential to modulate the acute phase response and cross the blood brain barrier, their contribution to neuroinflammation during systemic infection is unknown. The objective of this study was to elucidate the mechanisms by which lipoprotein subclasses modulate lipopolysaccharide (LPS)-induced neuroinflammation. Adult C57BL/6 mice were divided into 6 treatment groups, including a sterile saline vehicle control group (n = 9), an LPS group (n = 11), a premixed LPS + HDL group (n = 6), a premixed LPS + LDL group (n = 5), a HDL only group (n = 6) and an LDL only group (n = 3). In all cases injections were administered intraperitoneally. LPS was administered at 0.5 mg/kg, and lipoproteins were administered at 20 mg/kg. Behavioural testing and tissue collection was performed 6 h post-injection. The magnitude of peripheral and central inflammation was determined by qPCR of pro-inflammatory genes in fresh liver and brain. Metabolite profiles of liver, plasma and brain were determined by (1)H NMR. Endotoxin concentration in the brain was measured by the Limulus Amoebocyte Lysate (LAL) assay. Co-administration of LPS + HDL exacerbated both peripheral and central inflammation, whilst LPS + LDL attenuated this inflammation. Metabolomic analysis identified several metabolites significantly associated with LPS-induced inflammation, which were partially rescued by LDL, but not HDL. Endotoxin was detected at significantly greater concentrations in the brains of animals that received LPS + HDL compared to LPS + saline, but not those that received LPS + LDL. These results suggest that HDL may promote neuroinflammation through direct shuttling of endotoxin to the brain. In contrast, LDL was shown to have anti-neuroinflammatory properties in this study. Our results indicate that lipoproteins may be useful targets in neuroinflammation and neurodegeneration associated with endotoxemia and sepsis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12944-023-01817-z. |
format | Online Article Text |
id | pubmed-10124044 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-101240442023-04-25 HDL and LDL have distinct, opposing effects on LPS-induced brain inflammation Radford-Smith, Daniel E. Yates, Abi G. Rizvi, Laila Anthony, Daniel C. Probert, Fay Lipids Health Dis Research Endotoxemia and sepsis induce neuroinflammation and increase the risk of neurodegenerative disorders although the mechanism by which peripheral infection leads to brain inflammation is not well understood. While circulating serum lipoproteins are known immunometabolites with the potential to modulate the acute phase response and cross the blood brain barrier, their contribution to neuroinflammation during systemic infection is unknown. The objective of this study was to elucidate the mechanisms by which lipoprotein subclasses modulate lipopolysaccharide (LPS)-induced neuroinflammation. Adult C57BL/6 mice were divided into 6 treatment groups, including a sterile saline vehicle control group (n = 9), an LPS group (n = 11), a premixed LPS + HDL group (n = 6), a premixed LPS + LDL group (n = 5), a HDL only group (n = 6) and an LDL only group (n = 3). In all cases injections were administered intraperitoneally. LPS was administered at 0.5 mg/kg, and lipoproteins were administered at 20 mg/kg. Behavioural testing and tissue collection was performed 6 h post-injection. The magnitude of peripheral and central inflammation was determined by qPCR of pro-inflammatory genes in fresh liver and brain. Metabolite profiles of liver, plasma and brain were determined by (1)H NMR. Endotoxin concentration in the brain was measured by the Limulus Amoebocyte Lysate (LAL) assay. Co-administration of LPS + HDL exacerbated both peripheral and central inflammation, whilst LPS + LDL attenuated this inflammation. Metabolomic analysis identified several metabolites significantly associated with LPS-induced inflammation, which were partially rescued by LDL, but not HDL. Endotoxin was detected at significantly greater concentrations in the brains of animals that received LPS + HDL compared to LPS + saline, but not those that received LPS + LDL. These results suggest that HDL may promote neuroinflammation through direct shuttling of endotoxin to the brain. In contrast, LDL was shown to have anti-neuroinflammatory properties in this study. Our results indicate that lipoproteins may be useful targets in neuroinflammation and neurodegeneration associated with endotoxemia and sepsis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12944-023-01817-z. BioMed Central 2023-04-24 /pmc/articles/PMC10124044/ /pubmed/37095493 http://dx.doi.org/10.1186/s12944-023-01817-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Radford-Smith, Daniel E. Yates, Abi G. Rizvi, Laila Anthony, Daniel C. Probert, Fay HDL and LDL have distinct, opposing effects on LPS-induced brain inflammation |
title | HDL and LDL have distinct, opposing effects on LPS-induced brain inflammation |
title_full | HDL and LDL have distinct, opposing effects on LPS-induced brain inflammation |
title_fullStr | HDL and LDL have distinct, opposing effects on LPS-induced brain inflammation |
title_full_unstemmed | HDL and LDL have distinct, opposing effects on LPS-induced brain inflammation |
title_short | HDL and LDL have distinct, opposing effects on LPS-induced brain inflammation |
title_sort | hdl and ldl have distinct, opposing effects on lps-induced brain inflammation |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10124044/ https://www.ncbi.nlm.nih.gov/pubmed/37095493 http://dx.doi.org/10.1186/s12944-023-01817-z |
work_keys_str_mv | AT radfordsmithdaniele hdlandldlhavedistinctopposingeffectsonlpsinducedbraininflammation AT yatesabig hdlandldlhavedistinctopposingeffectsonlpsinducedbraininflammation AT rizvilaila hdlandldlhavedistinctopposingeffectsonlpsinducedbraininflammation AT anthonydanielc hdlandldlhavedistinctopposingeffectsonlpsinducedbraininflammation AT probertfay hdlandldlhavedistinctopposingeffectsonlpsinducedbraininflammation |