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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
Cites
Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144
The chemokine system in diverse forms of macrophage activation and polarization
MANTOVANI, A., SICA, A., SOZZANI, S., ALLAVENA, P., VECCHI, A., & LOCATI, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.09.015 · Cited by 6,534
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110
ATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913
Transcriptional regulation of macrophage polarization: enabling diversity with identity
Lawrence, T., & Natoli, G. (2011) · Nature Reviews Immunology · doi:10.1038/nri3088 · Cited by 2,284
Inflammation after trauma: Microglial activation and traumatic brain injury
Ramlackhansingh, A. F., Brooks, D. J., Greenwood, R. J., Bose, S. K., Turkheimer, F. E., Kinnunen, K. M., Gentleman, S., Heckemann, R. A., Gunanayagam, K., Gelosa, G., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22455 · Cited by 999
El Khoury, J., Toft, M., Hickman, S. E., Means, T. K., Terada, K., Geula, C., & Luster, A. D. (2007) · Nature Medicine · doi:10.1038/nm1555 · Cited by 915
Heterogeneity of CNS myeloid cells and their roles in neurodegeneration
Prinz, M., Priller, J., Sisodia, S. S., & Ransohoff, R. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2923 · Cited by 674
Saederup, N., Cardona, A. E., Croft, K., Mizutani, M., Cotleur, A. C., Tsou, C.-L., Ransohoff, R. M., & Charo, I. F. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013693 · Cited by 599
Research works printed but not linked: 48
- 10.1126/science.1142883 · DOI · Paper page
- 10.1146/annurev.immunol.021908.132557 · DOI
- 10.2119/2008-00050.Beauchamp · DOI
- 10.1016/j.bbi.2011.07.225 · DOI
- 10.1158/0008-5472.CAN-12-2989 · DOI
- 10.1172/JCI34613 · DOI
- 10.1016/j.expneurol.2006.10.013 · DOI
- 10.1016/j.neuroscience.2012.08.058 · DOI
- 10.1038/nprot.2006.327 · DOI · Paper page
- 10.1016/j.brainres.2012.08.032 · DOI
- 10.1007/s11481-009-9164-4 · DOI
- 10.1186/1479-5876-5-11 · DOI · Paper page
- 10.1371/journal.pone.0059712 · DOI
- 10.1136/jnnp.74.7.857 · DOI · Paper page
- 10.1523/JNEUROSCI.4070-13.2014 · DOI · Paper page
- 10.2174/157015912804499483 · DOI
- 10.1002/eji.201243084 · DOI
- 10.1096/fj.05-5465com · DOI
- 10.1089/neu.2008.0562 · DOI
- 10.1093/brain/aws322 · DOI · Paper page
- 10.1523/JNEUROSCI.3257-09.2009 · DOI · Paper page
- 10.1182/blood-2008-07-168575 · DOI · Paper page
- 10.1089/neu.2012.2589 · DOI
- 10.4049/jimmunol.166.7.4697 · DOI
- 10.4049/jimmunol.1100421 · DOI · Paper page
- 10.1523/JNEUROSCI.0539-12.2012 · DOI
- 10.1371/journal.pone.0093650 · DOI
- 10.1016/j.injury.2007.10.005 · DOI · Paper page
- 10.1089/neu.2011.2188 · DOI
- 10.1016/S0140-6736(14)60341-X · DOI
- 10.1016/j.jneuroim.2010.05.015 · DOI · Paper page
- 10.1016/S0165-0173(99)00007-7 · DOI
- 10.1002/1097-4547(20010301)63:5<438::AID-JNR1039>3.0.CO;2-P · DOI
- 10.1523/JNEUROSCI.4469-04.2005 · DOI
- 10.1093/brain/awp148 · DOI
- 10.1016/j.brainres.2009.06.054 · DOI
- 10.1002/hep.22952 · DOI
- 10.1038/ni1309 · DOI
- 10.1016/j.immuni.2013.02.012 · DOI · Paper page
- 10.1016/j.neubiorev.2012.02.013 · DOI · Paper page
- 10.1089/neu.1995.12.169 · DOI · Paper page
- 10.4049/jimmunol.0802812 · DOI
- 10.1186/1742-2094-2-24 · DOI
- 10.1038/jcbfm.2013.146 · DOI · Paper page
- 10.3389/fneur.2013.00018 · DOI
- 10.1073/pnas.0937239100 · DOI
- 10.1371/journal.pone.0034504 · DOI · Paper page
- 10.1016/j.nurt.2009.10.016 · DOI
Cited by
Sorted by citations
Items 201–212 of 212
Mayilsamy, K., Patel, P. B., Green, R. J., Bikkasani, S., Tosi, K., Majumdar, S., Prajapati, S. K., Markoutsa, E., Wolf, T., Guergues, J., et al. (2026) · Molecular Therapy · doi:10.64898/2026.09.04.748639
Heart-brain interaction and research progress following traumatic brain injury
Shen, D., Huang, R., Wang, L., Pang, Q., Li, M., & Wang, T. Z. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.07.018
Infiltrating Monocyte Fate Switch in Retinal Degeneration: From Early Pathology to Late Homeostasis
Ma, W., Zhang, Q., Dong, L.-J., Tang, F., Ball, J. M., Nadal-Nicolás, F., Qian, H., Villasmil, R., Dagur, P. K., Tam, J., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9827841/v1
“This temporal distinction is critical as it suggests that therapeutic strategies targeting monocyte infiltration, such as CCR2 antagonism 58–60 , is best timed to coincide with the acute inflammatory window to be effective without disrupting long-term repair processes.”
Threja, S., Strogulski, N., Laabei, J., Vegliante, G., Douglas, C., Bogale, T. A., Moynihan, C., Franco, G. D., Mack, M., Borkner, L., et al. (2026) · bioRxiv · doi:10.64898/2026.03.23.713833
“CCR2-dependent monocytes and monocyte-derived macrophages contribute to post-TBI inflammatory polarization and cognitive impairments [29, 30], while CCR2 antagonism (using CCX872) reduces inflammatory macrophage accumulation and improves cognition, supporting a causal CCR2 inflammatory axis [30].”
GPR84 and Neuroinflammation: A Receptor Worth Targeting, or A Target Worth Reconsidering?
Jarco, J., & Małek, N. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-06132-z
“Gpr84 knockout mice exhibited attenuated pain hypersensitivity, reduced pro-inflammatory gene expression, and diminished infiltration of CD68 ⁺ macrophages, underscoring the receptor’s role in coordinating both resident microglia and infiltrating myeloid cells [13, 16, 25, 38].”
A Spatial Gene Expression Signature of the Mouse Brain Post-Injury at the Focal Point of Contusion
Kounelis-Wuillaume, S., Frank, A. M., Goguet, E., Alba, C., Sukumar, G., Wilkerson, M. D., Dalgard, C. L., McCabe, J. T., & Doughty, M. L. (2025) · Journal of Neurotrauma · doi:10.1177/08977151251390528 · Cited by 1
“85 – 87 For example, Ccl12 deletion does not have a detectable impact on monocyte traf fi cking under homeostatic conditions, 88 and yet upregulation of Ccl12 has been identi fi ed as a possible driver of increased Ccr2 + monocyte in fi ltration and exacerbated memory dysfunction in aged mice…”
Lipinski, M. M., Mehrabani-Tabari, A. A., Hegdekar, N., Herb, B. R., Kachi, S. A., Sarkar, C., Thapa, S., Nguyen, D., Morel, Y., Weldemariam, M., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-7682363/v1
Wibisono, D. P., Arfian, N., Munawaroh, F., & Sari, D. C. R. (2025) · Indonesian Journal of Biomedicine and Clinical Sciences · doi:10.22146/inajbcs.v57i3.12757
Fridh, P., Katsler, E., Marklund, N., Mangsbo, S., & Ebendal, T. (2025) · Neurotrauma Reports · doi:10.1177/2689288x251396704
“21 These recruited cells are expressing the integrin heterodimer Itgax/Itgb2 (CD11c/CD18), mediating binding to cell adhesion molecules (like ICAM-1) fostering transendothelial migration.”
Littlejohn, E. L. (2018) · UKnowledge (University of Kentucky) · doi:10.13023/etd.2018.292
“On day 1 (acquisition day), mice were trained over four blocks of 3 trials to identify the platform location, alternating between visible and hidden platform trials (Morganti et al. 2015).”
MethodCerebral Atrophy and Leukoencephalopathy Following Cranial Irradiation
Prust, M., & Dietrich, J. (2018) · Springer eBooks · doi:10.1007/978-3-319-42878-9_39
Nguyen, H., Liska, M. G., Crowley, M. G., & Borlongan, C. V. (2017) · Springer series in translational stroke research · doi:10.1007/978-3-319-66679-2_8
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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