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Published on: September 26, 2018
Low-Density Lipoprotein Receptor Deficiency Attenuates Neuroinflammation through the Induction of Apolipoprotein E
Jo Mailleux1, Silke Timmermans1, Katherine Nelissen1
1Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
Objective:
We aimed to determine the role of the low-density lipoprotein receptor (LDLr) in neuroinflammation by inducing experimental autoimmune encephalomyelitis (EAE) in ldlr knock out mice.
Methods:
MOG35-55 induced EAE in male and female ldlr-/- mice was assessed clinically and histopathologically. Expression of inflammatory mediators and apolipoprotein E (apoE) was investigated by qPCR. Changes in protein levels of apoE and tumor necrosis factor alpha (TNFα) were validated by western blot and ELISA, respectively.
Results:
Ldlr-/--attenuated EAE disease severity in female, but not in male, EAE mice marked by a reduced proinflammatory cytokine production in the central nervous system of female ldlr-/- mice. Macrophages from female ldlr-/- mice showed a similar decrease in proinflammatory mediators, an impaired capacity to phagocytose myelin and enhanced secretion of the anti-inflammatory apoE. Interestingly, apoE/ldlr double knock out abrogated the beneficial effect of ldlr depletion in EAE.
Conclusion:
Collectively, we show that ldlr-/- reduces EAE disease severity in female but not in male EAE mice, and that this can be explained by increased levels of apoE in female ldlr-/- mice. Although the reason for the observed sexual dimorphism remains unclear, our findings show that LDLr and associated apoE levels are involved in neuroinflammatory processes.
Insights
Low-density lipoprotein receptor (LDLr) deficiency attenuated experimental autoimmune encephalomyelitis (EAE) in female mice by increasing apolipoprotein E (apoE). This highlights LDLr
Area of Science:
- Neuroimmunology
- Lipid Metabolism
- Autoimmune Diseases
Background:
- Neuroinflammation is a key component of multiple sclerosis and other neurological disorders.
- The low-density lipoprotein receptor (LDLr) plays a role in cholesterol homeostasis.
- The involvement of LDLr in neuroinflammatory processes remains incompletely understood.
Purpose of the Study:
- To investigate the role of LDLr in neuroinflammation using a mouse model of experimental autoimmune encephalomyelitis (EAE).
- To determine the impact of LDLr deficiency on EAE disease severity and underlying inflammatory mechanisms.
Main Methods:
- Induction of MOG35-55 EAE in LDLr knockout (ldlr-/-) mice (male and female).
- Clinical and histopathological assessment of EAE.
- Quantitative PCR (qPCR) for inflammatory mediators and apolipoprotein E (apoE).
- Western blot and ELISA for apoE and TNFα protein levels.
Main Results:
- LDLr deficiency attenuated EAE severity in female mice, but not in males.
- Female ldlr-/- mice exhibited reduced central nervous system proinflammatory cytokine production.
- Macrophages from female ldlr-/- mice showed decreased proinflammatory mediators, impaired myelin phagocytosis, and enhanced apoE secretion.
- ApoE/LDLr double knockout abrogated the protective effect of LDLr depletion in EAE.
Conclusions:
- LDLr deficiency reduces EAE severity in female mice, linked to increased apoE levels.
- The observed sexual dimorphism in EAE response warrants further investigation.
- LDLr and apoE are implicated in modulating neuroinflammatory processes.
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