Low-Density Lipoprotein Receptor Deficiency Attenuates Neuroinflammation through the Induction of Apolipoprotein E.

Jo Mailleux,Jasmine Vanmol,Jerome J A Hendriks,Silke Timmermans,Jeroen F J Bogie,Katherine Nelissen,Tim Vanmierlo,Jack Van Horssen

doi:10.3389/fimmu.2017.01701

Jo Mailleux, Jasmine Vanmol + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2017.01701

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Abstract

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. 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. 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. 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.

Highlights

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease of the central nervous system (CNS)
We show that ldlr−/− attenuates neuroinflammation in female but not in male EAE mice, and that macrophages isolated from female mice have an attenuated inflammatory response and reduced phagocytic capacity
ApoE deficiency counteracts the impact of ldlr deficiency in females on the course and pathology of EAE

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease of the central nervous system (CNS). Increasing evidence indicates that phagocytes can acquire a disease-resolving phenotype in the CNS. We recently defined that ingestion of myelin by macrophages alters the inflammatory phenotype by activating the cholesterol- and fatty acid-sensing nuclear. Ldlr-/- Attenuates Neuroinflammation through apoE liver X receptors and peroxisome proliferator-activated receptors [8,9,10]. These studies stress the pleiotropic role that phagocytes play in the pathophysiology of MS and indicate that lipid-signaling pathways drive the phenotype of phagocytes in MS lesions

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