title: Chronic expression of monocyte chemoattractant protein-1 in the central nervous system causes delayed encephalopathy and impaired microglial function in mice.
abstract: Increased central nervous system (CNS) levels of monocyte chemoattractant protein 1 [CC chemokine ligand 2 (CCL2) in the systematic nomenclature] have been reported in chronic neurological diseases such as human immunodeficiency virus type 1-associated dementia, amyotrophic lateral sclerosis, and multiple sclerosis. However, a pathogenic role for CCL2 has not been confirmed, and there is no established model for the effects of chronic CCL2 expression on resident and recruited CNS cells. We report that aged (>6 months) transgenic (tg) mice expressing CCL2 under the control of the human glial fibrillary acidic protein promoter (huGFAP-CCL2hi tg+ mice) manifested encephalopathy with mild perivascular leukocyte infiltration, impaired blood brain barrier function, and increased CD45-immunoreactive microglia, which had morphologic features of activation. huGFAP-CCL2hi tg+ mice lacking CC chemokine receptor 2 (CCR2) were normal, showing that chemokine action via CCR2 was required. Studies of cortical slice preparations using video confocal microscopy showed that microglia in the CNS of huGFAP-CCL2hi tg+ mice were defective in expressing amoeboid morphology. Treatment with mutant CCL2 peptides, a receptor antagonist and an obligate monomer, also suppressed morphological transformation in this assay, indicating a critical role for CCL2 in microglial activation and suggesting that chronic CCL2 exposure desensitized CCR2 on microglia, which in the CNS of huGFAP-CCL2hi tg+ mice, did not up-regulate cell-surface expression of major histocompatibility complex class II, CD11b, CD11c, or CD40, in contrast to recruited perivascular macrophages that expressed enhanced levels of these markers. These results indicate that huGFAP-CCL2hi tg+ mice provide a useful model to study how chronic CNS expression of CCL2 alters microglial function and CNS physiology.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Deren
authors.initials: D
authors.lastname: Huang
authors.forename: Jerome
authors.initials: J
authors.lastname: Wujek
authors.forename: Graham
authors.initials: G
authors.lastname: Kidd
authors.forename: Toby T
authors.initials: TT
authors.lastname: He
authors.forename: Astrid
authors.initials: A
authors.lastname: Cardona
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Sasse
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Stein
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Kish
authors.forename: Marie
authors.initials: M
authors.lastname: Tani
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Proudfoot
authors.forename: Barrett J
authors.initials: BJ
authors.lastname: Rollins
authors.forename: Tracy
authors.initials: T
authors.lastname: Handel
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002490:Central Nervous System / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000737:chemistry / Q000473:pathology; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D003433:Crosses, Genetic; D005434:Flow Cytometry; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D018613:Microscopy, Confocal; D009185:Myelin Proteins / Q000032:analysis / Q000276:immunology; D009422:Nervous System Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016900:Neurofilament Proteins / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency; D015398:Signal Transduction; D013116:Spinal Cord / Q000737:chemistry / Q000473:pathology
chemical_list: C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; D009185:Myelin Proteins; D016900:Neurofilament Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1