title: MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells.
abstract: Multifocal inflammatory lesions featuring destruction of lipid-rich myelin are pathologic hallmarks of multiple sclerosis. Lesion activity is assessed by the extent and composition of myelin uptake by myeloid cells present in such lesions. In the inflamed CNS, myeloid cells are comprised of brain-resident microglia, an endogenous cell population, and monocyte-derived macrophages, which infiltrate from the systemic compartment. Using microglia isolated from the adult human brain, we demonstrate that myelin phagocytosis is dependent on the polarization state of the cells. Myelin ingestion is significantly enhanced in cells exposed to TGF-β compared with resting basal conditions and markedly reduced in classically activated polarized cells. Transcriptional analysis indicated that TGF-β-treated microglia closely resembled M0 cells. The tyrosine kinase phagocytic receptor MerTK was one of the most upregulated among a select number of differentially expressed genes in TGF-β-treated microglia. In contrast, MerTK and its known ligands, growth arrest-specific 6 and Protein S, were downregulated in classically activated cells. MerTK expression and myelin phagocytosis were higher in CNS-derived microglia than observed in monocyte-derived macrophages, both basally and under all tested polarization conditions. Specific MerTK inhibitors reduced myelin phagocytosis and the resultant anti-inflammatory biased cytokine responses for both cell types. Defining and modulating the mechanisms that regulate myelin phagocytosis has the potential to impact lesion and disease evolution in multiple sclerosis. Relevant effects would include enhancing myelin clearance, increasing anti-inflammatory molecule production by myeloid cells, and thereby permitting subsequent tissue repair.
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Luke M
authors.identifier: http://orcid.org/0000-0001-9496-2216
authors.initials: LM
authors.lastname: Healy
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Gabrielle
authors.identifier: http://orcid.org/0000-0003-1150-7483
authors.initials: G
authors.lastname: Perron
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: So-Yoon
authors.identifier: http://orcid.org/0000-0001-6633-1206
authors.initials: SY
authors.lastname: Won
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Mackenzie A
authors.identifier: http://orcid.org/0000-0001-8712-2665
authors.initials: MA
authors.lastname: Michell-Robinson
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Ayman
authors.initials: A
authors.lastname: Rezk
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada;
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Ludwin
authors.affiliation: Division of BioMedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada; and.
authors.forename: Craig S
authors.identifier: http://orcid.org/0000-0003-3333-435X
authors.initials: CS
authors.lastname: Moore
authors.affiliation: Department of Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Jeffery A
authors.identifier: http://orcid.org/0000-0001-8403-8986
authors.initials: JA
authors.lastname: Hall
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada; jack.antel@mcgill.ca.
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
mesh_terms: D000328:Adult; D001921:Brain / Q000166:cytology / Q000276:immunology; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D017628:Microglia / Q000166:cytology / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D009186:Myelin Sheath / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*; D017293:Protein S / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D016212:Transforming Growth Factor beta; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C097072:MERTK protein, human