Abstract
Objective: To document functional differences between monocyte-derived macrophages (MDMs) of patients with MS and the ability of age/sex-matched healthy donor cells to phagocytose human myelin and to investigate the molecular mechanisms that underlie this.
Methods: MDMs were derived from peripheral blood monocytes of 25 untreated patients with relapsing-remitting MS and secondary progressive MS and age/sex-matched healthy controls (HCs). Phagocytosis was assessed by flow cytometry using fluorescently labeled human myelin. Quantification of messenger RNA and protein expression of Tyro3, Axl, and MerTK family molecules was determined by quantitative PCR, Western blotting, and flow cytometry.
Results: Cells of patients with MS display a reduced ability to phagocytose human myelin but not red blood cells as compared to matched HCs. These cells express significantly lower levels of the phagocytic tyrosine kinase receptor, MerTK, and its natural ligand, growth arrest-specific 6, independently of the activation state of the cells. Increased expression of interleukin 10 following myelin uptake by healthy donor cells is lost in MDMs of patients with MS; this effect is mediated through the MerTK pathway. Treatment of MS cells with transforming growth factor β (TGFβ) restored both phagocytosis and expression deficits.
Conclusions: We describe a molecular mechanism that underlies a defect in myelin phagocytosis by macrophages generated from patients with MS. This abnormality involves decreased expression of MerTK and its ligands and can be rescued by treatment with TGFβ.
GLOSSARY
- FBS=
- fetal bovine serum;
- Gas6=
- growth arrest-specific 6;
- HC=
- healthy control;
- IL-10=
- interleukin 10;
- MDM=
- monocyte-derived-macrophage;
- mRNA=
- messenger RNA;
- PBS=
- phosphate-buffered saline;
- PPAR-γ=
- peroxisome proliferator–activated receptor gamma;
- ProS=
- protein S;
- PS=
- phosphatidylserine;
- RBC=
- red blood cell;
- RRMS=
- relapsing-remitting MS;
- RXR=
- retinoid X receptor;
- SPMS=
- secondary progressive MS;
- TAM=
- Tyro3, Axl, and MerTK;
- TGFβ=
- transforming growth factor β
Footnotes
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the authors.
- Received June 6, 2017.
- Accepted in final form August 9, 2017.
- Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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