title: LRP1 expression in microglia is protective during CNS autoimmunity.
abstract: Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis.
authors.affiliation: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.|Graduate Program in Pathology, University of Virginia, Charlottesville, VA, USA.|Medical Scientist Training Program, University of Virginia, Charlottesville, VA, USA.
authors.forename: Tzu-Ying
authors.initials: TY
authors.lastname: Chuang
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.|Medical Scientist Training Program, University of Virginia, Charlottesville, VA, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Seki
authors.affiliation: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
authors.forename: Abagail M
authors.initials: AM
authors.lastname: Rosen
authors.affiliation: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Johanson
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Mandell
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Claudia F
authors.initials: CF
authors.lastname: Lucchinetti
authors.affiliation: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. ag7h@virginia.edu.
authors.forename: Alban
authors.initials: A
authors.lastname: Gaultier
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000502:physiology; D001921:Brain / Q000276:immunology / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology* / Q000473:pathology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010243:Paralysis / Q000276:immunology / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins
keywords: Inflammation; LRP1; Microglia; Multiple sclerosis; NF-kB