CD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammation.
CD36
Fatty acid
Macrophages
Microglia
Multiple sclerosis
Myelin
Neuroinflammation
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
27 Jul 2020
27 Jul 2020
Historique:
received:
12
03
2020
accepted:
15
07
2020
entrez:
29
7
2020
pubmed:
29
7
2020
medline:
5
6
2021
Statut:
epublish
Résumé
The presence of foamy macrophages and microglia containing intracellular myelin remnants is a pathological hallmark of neurodegenerative disorders such as multiple sclerosis (MS). Despite the importance of myelin internalization in affecting both central nervous system repair and neuroinflammation, the receptors involved in myelin clearance and their impact on the phagocyte phenotype and lesion progression remain to be clarified. Flow cytometry, quantitative PCR, and immunohistochemistry were used to define the mRNA and protein abundance of CD36 in myelin-containing phagocytes. The impact of CD36 and nuclear factor erythroid 2-related factor 2 (NRF2) on the phagocytic and inflammatory features of macrophages and microglia was assessed using a pharmacological CD36 inhibitor (sulfo-N-succinimidyl oleate) and Nrf2 Here, we show that the fatty acid translocase CD36 is required for the uptake of myelin debris by macrophages and microglia, and that myelin internalization increased CD36 expression through NRF2. Pharmacological inhibition of CD36 promoted the inflammatory properties of myelin-containing macrophages and microglia in vitro, which was paralleled by a reduced activity of the anti-inflammatory lipid-sensing liver X receptors and peroxisome proliferator-activated receptors. By using the EAE model, we provide evidence that CD36 is essential for myelin debris clearance in vivo. Importantly, CD36 inhibition markedly increased the neuroinflammatory burden and disease severity in the EAE model. Altogether, we show for the first time that CD36 is crucial for clearing myelin debris and suppressing neuroinflammation in demyelinating disorders such as MS.
Sections du résumé
BACKGROUND
BACKGROUND
The presence of foamy macrophages and microglia containing intracellular myelin remnants is a pathological hallmark of neurodegenerative disorders such as multiple sclerosis (MS). Despite the importance of myelin internalization in affecting both central nervous system repair and neuroinflammation, the receptors involved in myelin clearance and their impact on the phagocyte phenotype and lesion progression remain to be clarified.
METHODS
METHODS
Flow cytometry, quantitative PCR, and immunohistochemistry were used to define the mRNA and protein abundance of CD36 in myelin-containing phagocytes. The impact of CD36 and nuclear factor erythroid 2-related factor 2 (NRF2) on the phagocytic and inflammatory features of macrophages and microglia was assessed using a pharmacological CD36 inhibitor (sulfo-N-succinimidyl oleate) and Nrf2
RESULTS
RESULTS
Here, we show that the fatty acid translocase CD36 is required for the uptake of myelin debris by macrophages and microglia, and that myelin internalization increased CD36 expression through NRF2. Pharmacological inhibition of CD36 promoted the inflammatory properties of myelin-containing macrophages and microglia in vitro, which was paralleled by a reduced activity of the anti-inflammatory lipid-sensing liver X receptors and peroxisome proliferator-activated receptors. By using the EAE model, we provide evidence that CD36 is essential for myelin debris clearance in vivo. Importantly, CD36 inhibition markedly increased the neuroinflammatory burden and disease severity in the EAE model.
CONCLUSION
CONCLUSIONS
Altogether, we show for the first time that CD36 is crucial for clearing myelin debris and suppressing neuroinflammation in demyelinating disorders such as MS.
Identifiants
pubmed: 32718316
doi: 10.1186/s12974-020-01899-x
pii: 10.1186/s12974-020-01899-x
pmc: PMC7384221
doi:
Substances chimiques
CD36 Antigens
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
224Subventions
Organisme : Fonds Wetenschappelijk Onderzoek
ID : 12J9116N, 12JG119N, 12U7718N, and G099618N
Organisme : Belgian Charcot Foundation
ID : FCS-2016-EG7, R-8676, and R-6832
Références
J Lipid Res. 2011 Mar;52(3):419-34
pubmed: 21062955
Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2333-8
pubmed: 15486305
Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22
pubmed: 9240432
J Neurosci. 2005 Mar 9;25(10):2504-12
pubmed: 15758158
J Clin Invest. 2000 Apr;105(8):1049-56
pubmed: 10772649
J Neuroimmunol. 1998 Dec 1;92(1-2):67-75
pubmed: 9916881
J Biol Chem. 2015 Jun 12;290(24):14852-65
pubmed: 25918169
Atherosclerosis. 2007 May;192(1):123-30
pubmed: 16919281
Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
pubmed: 12184808
Acta Neuropathol Commun. 2018 Nov 19;6(1):124
pubmed: 30454040
Nature. 2001 May 10;411(6834):207-11
pubmed: 11346799
Sci Rep. 2017 Dec 22;7:46925
pubmed: 29271403
Biochem Biophys Res Commun. 2012 Jan 27;417(4):1304-9
pubmed: 22234309
Diabetes. 2014 Nov;63(11):3606-14
pubmed: 24917573
J Immunol. 2019 Apr 15;202(8):2189-2194
pubmed: 30850475
J Neurosci. 2017 Mar 1;37(9):2362-2376
pubmed: 28130359
Future Neurol. 2012 Mar 1;7(2):165-176
pubmed: 22737039
Biosci Biotechnol Biochem. 2014;78(2):238-44
pubmed: 25036676
J Exp Med. 2014 Jul 28;211(8):1533-49
pubmed: 25002752
J Biol Chem. 2001 Nov 23;276(47):44222-8
pubmed: 11564734
J Biol Chem. 2000 Oct 20;275(42):32523-9
pubmed: 10913136
PLoS One. 2012;7(9):e44998
pubmed: 22984598
Curr Opin Infect Dis. 2008 Jun;21(3):271-8
pubmed: 18448972
J Neurosci. 2015 Apr 22;35(16):6532-43
pubmed: 25904803
Nat Neurosci. 2013 Sep;16(9):1211-1218
pubmed: 23872599
Biochim Biophys Acta. 1999 Jan 4;1436(3):279-98
pubmed: 9989260
Cell Stem Cell. 2012 Jan 6;10(1):96-103
pubmed: 22226359
J Biol Chem. 2015 Feb 20;290(8):4590-603
pubmed: 25555908
Science. 2018 Feb 9;359(6376):684-688
pubmed: 29301957
J Neuroinflammation. 2011 Jul 25;8:85
pubmed: 21781347
Malar J. 2015 Sep 18;14:358
pubmed: 26385579
Acta Neuropathol. 2014 Aug;128(2):191-213
pubmed: 24952885
J Neurosci Res. 2006 Sep;84(4):874-90
pubmed: 16868960
J Immunol. 2016 Apr 15;196(8):3375-84
pubmed: 26962228
J Cell Sci. 2009 Apr 15;122(Pt 8):1155-62
pubmed: 19299462
Mol Biol Cell. 2005 Jan;16(1):24-31
pubmed: 15496455
Gastroenterology. 2008 Feb;134(2):556-67
pubmed: 18242221
Front Immunol. 2018 Jan 30;9:127
pubmed: 29441073
Brain. 2006 Feb;129(Pt 2):517-26
pubmed: 16364958
Front Immunol. 2017 Nov 30;8:1701
pubmed: 29276512
J Exp Med. 2020 May 4;217(5):
pubmed: 32097464
J Exp Med. 2015 Apr 6;212(4):481-95
pubmed: 25779633
Circ Res. 2004 Mar 19;94(5):609-16
pubmed: 14752028
J Biomed Opt. 2011 Oct;16(10):106006
pubmed: 22029353
Mult Scler. 2018 Mar;24(3):279-289
pubmed: 28273782
J Biol Chem. 2008 Dec 12;283(50):34554-62
pubmed: 18940800
PLoS Pathog. 2011 Sep;7(9):e1002254
pubmed: 21949655
Arterioscler Thromb Vasc Biol. 1999 May;19(5):1333-9
pubmed: 10323787
Annu Rev Nutr. 2014;34:281-303
pubmed: 24850384
Acta Neuropathol Commun. 2013 Aug 02;1:43
pubmed: 24252308
Sci Rep. 2017 Mar 20;7:44794
pubmed: 28317919
Cell Mol Neurobiol. 1996 Aug;16(4):517-28
pubmed: 8879753