title: CCR2 antagonism alters brain macrophage polarization and ameliorates cognitive dysfunction induced by traumatic brain injury.
abstract: Traumatic brain injury (TBI) is a major risk factor for the development of multiple neurodegenerative diseases. With respect to the increasing prevalence of TBI, new therapeutic strategies are urgently needed that will prevent secondary damage to primarily unaffected tissue. Consistently, neuroinflammation has been implicated as a key mediator of secondary damage following the initial mechanical insult. Following injury, there is uncertainty regarding the role that accumulating CCR2(+) macrophages play in the injury-induced neuroinflammatory sequelae and cognitive dysfunction. Using CX3CR1(GFP/+)CCR2(RFP/+) reporter mice, we show that TBI initiated a temporally restricted accumulation of peripherally derived CCR2(+) macrophages, which were concentrated in the hippocampal formation, a region necessary for learning and memory. Multivariate analysis delineated CCR2(+) macrophages' neuroinflammatory response while identifying a novel therapeutic treatment window. As a proof of concept, targeting CCR2(+) macrophages with CCX872, a novel Phase I CCR2 selective antagonist, significantly reduced TBI-induced inflammatory macrophage accumulation. Concomitantly, there was a significant reduction in multiple proinflammatory and neurotoxic mediators with this treatment paradigm. Importantly, CCR2 antagonism resulted in a sparing of TBI-induced hippocampal-dependent cognitive dysfunction and reduced proinflammatory activation profile 1 month after injury. Thus, therapeutically targeting the CCR2(+) subset of monocytes/macrophages may provide a new avenue of clinical intervention following TBI.
authors.affiliation: Brain and Spinal Injury Center, Departments of Physical Therapy and Rehabilitation Science, and rosis@ptrehab.ucsf.edu josh.morganti@ucsf.edu.
authors.forename: Josh M
authors.initials: JM
authors.lastname: Morganti
authors.affiliation: Brain and Spinal Injury Center.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Jopson
authors.affiliation: Neurological Surgery, University of California, San Francisco, California 94110.
authors.forename: Sharon
authors.initials: S
authors.lastname: Liu
authors.affiliation: Brain and Spinal Injury Center.
authors.forename: Lara-Kirstie
authors.initials: LK
authors.lastname: Riparip
authors.affiliation: Brain and Spinal Injury Center.
authors.forename: Cristian K
authors.initials: CK
authors.lastname: Guandique
authors.affiliation: Neurological Surgery, University of California, San Francisco, California 94110.
authors.forename: Nalin
authors.identifier: http://orcid.org/0000-0001-9539-7052
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Brain and Spinal Injury Center, Neurological Surgery, University of California, San Francisco, California 94110.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Ferguson
authors.affiliation: Brain and Spinal Injury Center, Departments of Physical Therapy and Rehabilitation Science, and Neurological Surgery, University of California, San Francisco, California 94110 rosis@ptrehab.ucsf.edu josh.morganti@ucsf.edu.
authors.forename: Susanna
authors.initials: S
authors.lastname: Rosi
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy*; D000073883:CX3C Chemokine Receptor 1; D003071:Cognition; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000503:physiopathology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054390:Receptors, CCR2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515335:Ccr2 protein, mouse; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine
keywords: CCR2; PCA; TBI; inflammation; macrophage; therapeutic