title: Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and subsequent deposition of amyloid (Aβ) within the brain. The brain's immune cells migrate to and invest their processes within Aβ plaques but are unable to efficiently phagocytose and clear plaques from the brain. Previous studies have shown that treatment of myeloid cells with nuclear receptor agonists increases expression of phagocytosis-related genes. In this study, we elucidate a novel mechanism by which nuclear receptors act to enhance phagocytosis in the AD brain. Treatment of murine models of AD with agonists of the nuclear receptors PPARγ, PPARδ, LXR, and RXR stimulated microglial phagocytosis in vitro and rapidly induced the expression of the phagocytic receptors Axl and MerTK. In murine models of AD, we found that plaque-associated macrophages expressed Axl and MerTK and treatment of the cells with an RXR agonist further induced their expression, coincident with the rapid reduction in plaque burden. Further characterization of MerTK(+)/Axl(+) macrophages revealed that they also expressed the phagocytic receptor TREM2 and high levels of CD45, consistent with a peripheral origin of these cells. Importantly, in an ex vivo slice assay, nuclear receptor agonist treatment reversed the AD-related suppression of phagocytosis through a MerTK-dependent mechanism. Thus, nuclear receptor agonists increase MerTK and Axl expression on plaque-associated immune cells, consequently licensing their phagocytic activity and promoting plaque clearance.
authors.affiliation: Departments of Neurosciences.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Savage
authors.affiliation: Departments of Neurosciences, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and.
authors.forename: Taylor
authors.initials: T
authors.lastname: Jay
authors.affiliation: Departments of Neurosciences.
authors.forename: Elanda
authors.initials: E
authors.lastname: Goduni
authors.affiliation: Departments of Neurosciences.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Quigley
authors.affiliation: Departments of Neurosciences.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mariani
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 80130 Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Departments of Neurosciences, Genetics, and Molecular Medicine, Case Western Reserve University, Cleveland, Ohio 44106, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and Cleveland Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Bruce T
authors.identifier: http://orcid.org/0000-0001-8507-2561
authors.initials: BT
authors.lastname: Lamb
authors.affiliation: Departments of Neurosciences, gel2@case.edu.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D000077610:Bexarotene; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D000077205:Pioglitazone; D058225:Plaque, Amyloid / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D001565:Benzoates; D001596:Benzylamines; D000077610:Bexarotene; D017493:Leukocyte Common Antigens; D008562:Membrane Glycoproteins; D000077205:Pioglitazone; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; C473027:GW 3965; C498716:Trem2 protein, mouse; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C490767:Mertk protein, mouse; C516770:Ptprc protein, mouse; C000722290:AXL receptor tyrosine kinase, mouse
keywords: Alzheimer's disease; microglia; nuclear receptors; phagocytosis