Sage Journals: Discover world-class research

Abstract

Objective:

We sought to determine the liver X receptor (LXR) ligands present in human macrophages after myelin phagocytosis and whether LXRs are activated in multiple sclerosis (MS) lesions.

Methods:

We used real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry to determine expression of LXRs and their response genes in human phagocytes after myelin phagocytosis and in active MS lesions. We used gas chromatographic/mass spectrometric analysis to determine LXR-activating oxysterols and cholesterol precursors present and formed in myelin and myelin-incubated cells, respectively.

Results:

Myelin induced LXR response genes ABCA1 and ABCG1 in human monocyte-derived macrophages. In active MS lesions, we found that both gene expression and protein levels of ABCA1 and apolipoprotein E (APOE) are upregulated in foamy phagocytes. Moreover, we found that the LXR ligand 27-hydroxycholesterol (27OHC) is significantly increased in human monocyte-derived macrophages after myelin uptake.

Conclusion:

LXR response genes are upregulated in phagocytes present in active MS lesions, indicating that LXRs are activated in actively demyelinating phagocytes. In addition, we have shown that myelin contains LXR ligands and that 27OHC is generated in human monocyte-derived macrophages after myelin processing. This suggests that LXRs in phagocytes in active MS lesions are activated at least partially by (oxy)sterols present in myelin and the generation thereof during myelin processing.

Keywords

Demyelinating diseases multiple sclerosis myelin sheath phagocytes liver X receptor 27-hydroxycholesterol

Get full access to this article

View all access options for this article.

References

Bar-Or

Oliveira

Anderson

et al . Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 1999; 100(1–2): 252–259.

Hendriks

Teunissen

de Vries

et al . Macrophages and neurodegeneration. Brain Res Brain Res Rev 2005; 48(2): 185–195.

Barnett

Henderson

Prineas

JW.

The macrophage in MS: Just a scavenger after all? Pathology and pathogenesis of the acute MS lesion. Mult Scler 2006; 12(2): 121–132.

Bogie

Stinissen

Hendriks

JJ.

Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathol 2014; 128(2): 191–213.

Kotter

Zhao

van Rooijen

et al . Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis 2005; 18(1): 166–175.

Schwab

ME.

Nogo and axon regeneration. Curr Opin Neurobiol 2004; 14(1): 118–124.

Morell

Quarles

RH.

Characteristic composition of myelin. In: Siegel

Agranoff

(eds) Basic neurochemistry: Molecular, cellular, and medical aspects. 6th ed. Philadelphia, PA: Lippincott-Raven, 1999.

Saher

Brugger

Lappe-Siefke

et al . High cholesterol level is essential for myelin membrane growth. Nat Neurosci 2005; 8(4): 468–475.

Spady

Dietschy

JM.

Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res 1983; 24(3): 303–315.

10.

Van

Kraats

Killestein

Popescu

et al . Oxysterols and cholesterol precursors correlate to magnetic resonance imaging measures of neurodegeneration in multiple sclerosis. Mult Scler 2014; 20(4): 412–417.

11.

Teunissen

Dijkstra

Polman

et al . Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients. Neurosci Lett 2003; 347(3): 159–162.

12.

Karrenbauer

Leoni

Lim

et al . Plasma cerebrosterol and magnetic resonance imaging measures in multiple sclerosis. Clin Neurol Neurosurg 2006; 108(5): 456–460.

13.

Zhao

Dahlman-Wright

Liver X receptor in cholesterol metabolism. J Endocrinol 2010; 204(3): 233–240.

14.

Fan

Kim

Bouton

et al . Expression of liver X receptor beta is essential for formation of superficial cortical layers and migration of later-born neurons. Proc Natl Acad Sci USA 2008; 105(36): 13445–13450.

15.

Joseph

Bradley

Castrillo

et al . LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 2004; 119(2): 299–309.

16.

Joseph

Castrillo

Laffitte

et al . Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 2003; 9(2): 213–219.

17.

Ghisletti

Huang

Ogawa

et al . Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol Cell 2007; 25(1): 57–70.

18.

Boven

Van Meurs

Van Zwam

et al . Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain 2006; 129(Pt 2): 517–526.

19.

Bogie

Stinissen

Hellings

et al . Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation. J Neuroinflammation 2011; 8: 85.

20.

Bogie

Jorissen

Mailleux

et al . Myelin alters the inflammatory phenotype of macrophages by activating PPARs. Acta Neuropathol Commun 2013; 1(1): 43.

21.

Bogie

Timmermans

Huynh-Thu

et al . Myelin-derived lipids modulate macrophage activity by liver X receptor activation. PLoS ONE 2012; 7(9): e44998.

22.

Norton

Poduslo

SE.

Myelination in rat brain: Changes in myelin composition during brain maturation. J Neurochem 1973; 21(4): 759–773.

23.

Jansen

Lutjohann

Abildayeva

et al . Dietary plant sterols accumulate in the brain. Biochim Biophys Acta 2006; 1761(4): 445–453.

24.

Lutjohann

Brzezinka

Barth

et al . Profile of cholesterol-related sterols in aged amyloid precursor protein transgenic mouse brain. J Lipid Res 2002; 43(7): 1078–1085.

25.

Vanmierlo

Bogie

Mailleux

et al . Plant sterols: Friend or foe in CNS disorders? Prog Lipid Res 2015; 58: 26–39.

26.

Yvan-Charvet

Wang

Tall

AR.

Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol 2010; 30(2): 139–143.

27.

Mangelsdorf

Evans

RM.

The RXR heterodimers and orphan receptors. Cell 1995; 83(6): 841–850.

28.

Janowski

Grogan

Jones

et al . Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci USA 1999; 96(1): 266–271.

29.

Menke

Chen

et al . 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 2001; 276(42): 38378–38387.

30.

Janowski

Willy

Devi

et al . An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 1996; 383(6602): 728–731.

31.

Forman

Ruan

Chen

et al . The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism. Proc Natl Acad Sci USA 1997; 94(20): 10588–10593.

32.

Zhou

Cummings

et al . Nuclear receptors have distinct affinities for coactivators: Characterization by fluorescence resonance energy transfer. Mol Endocrinol 1998; 12(10): 1594–1604.

33.

Castrillo

Joseph

Marathe

et al . Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages. J Biol Chem 2003; 278(12): 10443–10449.

34.

Meffre

Shackleford

Hichor

et al . Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum. Proc Natl Acad Sci USA 2015; 112(24): 7587–7592.

35.

Wang

Sadovnick

Traboulsee

et al . Nuclear receptor NR1H3 in familial multiple sclerosis. Neuron 2016; 90(5): 948–954.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.21 MB

0.42 MB

Active liver X receptor signaling in phagocytes in multiple sclerosis lesions

Abstract

Objective:

Methods:

Results:

Conclusion:

Keywords

Get full access to this article

References

Supplementary Material