title: The effect of inflammatory cell-derived MCP-1 loss on neuronal survival during chronic neuroinflammation.
abstract: Intracranial implants elicit neurodegeneration via the foreign body response (FBR) that includes BBB leakage, macrophage/microglia accumulation, and reactive astrogliosis, in addition to neuronal degradation that limit their useful lifespan. Previously, monocyte chemoattractant protein 1 (MCP-1, also CCL2), which plays an important role in monocyte recruitment and propagation of inflammation, was shown to be critical for various aspects of the FBR in a tissue-specific manner. However, participation of MCP-1 in the brain FBR has not been evaluated. Here we examined the FBR to intracortical silicon implants in MCP-1 KO mice at 1, 2, and 8 weeks after implantation. MCP-1 KO mice had a diminished FBR compared to WT mice, characterized by reductions in BBB leakage, macrophage/microglia accumulation, and astrogliosis, and an increased neuronal density. Moreover, pharmacological inhibition of MCP-1 in implant-bearing WT mice maintained the increased neuronal density. To elucidate the relative contribution of microglia and macrophages, bone marrow chimeras were generated between MCP-1 KO and WT mice. Increased neuronal density was observed only in MCP-1 knockout mice transplanted with MCP-1 knockout marrow, which indicates that resident cells in the brain are major contributors. We hypothesized that these improvements are the result of a phenotypic switch of the macrophages/microglia polarization state, which we confirmed using PCR for common activation markers. Our observations suggest that MCP-1 influences neuronal loss, which is integral to the progression of neurological disorders like Alzheimer's and Parkinson disease, via BBB leakage and macrophage polarization.
authors.affiliation: Department of Pathology, Yale School of Medicine, 310 Cedar Street LH 108, New Haven, CT 06520-8023, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sawyer
authors.affiliation: Bio-X Center, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, PR China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Tian
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Saucier-Sawyer
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rizk
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Bellamkonda
authors.affiliation: Department of Pathology, Yale School of Medicine, 310 Cedar Street LH 108, New Haven, CT 06520-8023, USA; Department of Biomedical Engineering, Yale University, New Haven, CT, USA. Electronic address: themis.kyriakides@yale.edu.
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism*; D002908:Chronic Disease; D005549:Foreign-Body Reaction / Q000628:therapy*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000628:therapy*; D009474:Neurons / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D019736:Prostheses and Implants; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023822:Tissue Engineering
chemical_list: D048588:Benzoxazines; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D010880:Piperidines; C573791:RS 102895; D054390:Receptors, CCR2
keywords: Foreign body response; MCP-1; Microglia polarization; Neurodegeneration