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CCR2 Antagonism Alters Brain Macrophage Polarization and Ameliorates Cognitive Dysfunction Induced by Traumatic Brain Injury
Open accessAbstract
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.
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“Separate groups have shown that CCX872 and RS504393, two selective CCR2 antagonists, reduce post-injury macrophage recruitment and improve functional recovery after CCI and weight drop TBI (76, 77).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [76]
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Citations
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Neuroinflammation: The Devil Is in the Details
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Background
Metadata
- Authors
- Morganti, J. M., Jopson, T. D., Liu, S., Riparip, L.-K., Guandique, C. K., Gupta, N., Ferguson, A. R., & Rosi, S.
- Affiliations
- University of California, San Francisco (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-01-14
- Volume
- 35
- Issue
- 2
- Pages
- 748-760
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4293420
- OpenAlex
- W2140178129
- Cited by
- 253
- References
- 71
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 17 · 2023: 15 · 2022: 21 · 2021: 30 · 2020: 35 · 2019: 26 · 2018: 32 · 2017: 19 · 2016: 23 · 2015: 10
- FWCI
- 19.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Alzheimer's Association (IIRG-11-202064)
- National Institutes of Health
- National Institute on Aging (R21AG042016)
- National Cancer Institute (R01CA133216)
- National Institute of Neurological Disorders and Stroke (R21NS087458, R01NS067092, F32NS090805)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, CCR2+ macrophages, macrophage polarization, neuroinflammation, cognitive impairment, hippocampus, monocytes, secondary injury, pro-inflammatory mediators
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Brain Injuries, Cognition, Female, Hippocampus, Macrophage Activation, Macrophages, Male, Mice, Inbred C57BL, Receptors, Chemokine, Mice, Receptors, CCR2
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