Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury
Open accessAbstract
BACKGROUND: Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes. METHODS: We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 (RFP/+) and Ccr2 (RFP/RFP) ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3 days later in order to determine the effects of altered monocyte entry into the brain. RESULTS: Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot. CONCLUSIONS: Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2(+) monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation.
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Interruption of CCR2 signaling through the use of Ccr2RFP/RFP mice reduces post-injury monocytic infiltration and axonal pathology but enhances cortical and hippocampal MAPT mislocalization and hyperphosphorylation soon after lateral fluid percussion TBI.
“Interruption of CCR2 signaling through the use of Ccr2RFP/RFP mice reduces post-injury monocytic infiltration and axonal pathology but enhances cortical and hippocampal MAPT mislocalization and hyperphosphorylation soon after lateral fluid percussion TBI suggesting that monocyte sub-populations may differentially influence outcome (78).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [78]
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“For example, it was shown that inhibition of CCR2 during TBI can limit lesion size; however, the same receptor is also responsible for the protection from tau pathologies [9].”
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“Interruption of CCR2 signaling through the use of Ccr2RFP/RFP mice reduces post-injury monocytic infiltration and axonal pathology but enhances cortical and hippocampal MAPT mislocalization and hyperphosphorylation soon after lateral fluid percussion TBI suggesting that monocyte sub-populations may differentially infl…”
BackgroundSelf-citationCross‐talk between monocyte invasion and astrocyte proliferation regulates scarring in brain injury
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Wu, J., Ren, R., Chen, T., Su, L., & Tang, T. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.111066 · Cited by 30 · see citing works
Harper, M. M., Rudd, D., Meyer, K. J., Kanthasamy, A., Anantharam, V., Pieper, A., Vázquez-Rosa, E., Shin, M.-K., Chaubey, K., Koh, Y., et al. (2020) · Heliyon · doi:10.1016/j.heliyon.2020.e03374 · Cited by 32 · see citing works
“Cellular mechanisms that are believed to lead to neuronal death and dysfunction after mild TBI or repetitive TBI include diffuse axonal injury and myelin damage, excitotoxicity, dysregulation of the neurovascular unit, inflammation, and oxidative stress [17, 18, 19, 20, 21].”
BackgroundKatsumoto, A., de Miranda, A. S., Butovsky, O., Teixeira, A. L., Ransohoff, R. M., & Lamb, B. T. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1075-y · Cited by 39 · see citing works
“Consistent with previous studies [18, 25], there was an increase in APP-positive profiles in the body of the corpus callosum as well as in hippocampus in the TBI-water group (Fig.”
InfluentialSelf-citationKokiko-Cochran, O. N., Saber, M., Puntambekar, S., Bemiller, S. M., Katsumoto, A., Lee, Y.-S., Bhaskar, K., Ransohoff, R. M., & Lamb, B. T. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5203 · Cited by 32 · see citing works
“01) as well as a significant genotype effect in Ly6c‐high expression cells (two way ANOVA, genotype effect, F(1, 14) = 7.”
Self-citationYagura, K., Ohtaki, H., Tsumuraya, T., Sato, A., Miyamoto, K., Kawada, N., Suzuki, K., Nakamura, M., Kanzaki, K., Dohi, K., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0230080 · Cited by 30 · see citing works
“Recent findings are consistent with our results: neutrophils polarized after infiltration can exert both beneficial and deleterious effects following tumorigenesis [45–47], stroke [48] and TBI [49].”
BackgroundInfluentialBennett, M., Chin, A., Lee, H. J., Cestero, E. M., Strazielle, N., Ghersi‐Egea, J., Threlkeld, S. W., Schmidt, T. A., Richendrfer, H. A., Szmydynger‐Chodobska, J., et al. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2020.7229 · Cited by 25 · see citing works
The therapeutic potential of bone marrow‐derived macrophages in neurological diseases
Zhou, K., Han, J., Wang, Y., Xu, Y., Zhang, Y., & Zhu, C. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13964 · Cited by 43 · see citing works
Wang, H., Huang, Q., Zhang, Z., Ji, J., Sun, T., & Wang, D. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02535-6 · Cited by 20 · see citing works
“However, another study has shown that CCR2 deletion in a TBI mouse model caused abnormally increased tau protein phosphorylation in the cortex and hippocampus, which is closely related to the loss of physiological function and the acquisition of pathological function in various neurodegenerative diseases [9].”
BackgroundPaladini, M. S., Yang, B. A., Torkenczy, K. A., Frias, E. S., Feng, X., Krukowski, K., Sit, R. V., Morri, M., Lam, W., Pedoia, V., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63952-8 · Cited by 19 · see citing works
Ethanol-induced damage to the developing spinal cord: The involvement of CCR2 signaling
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Alemán-Ruiz, C., Wang, W., Dingledine, R., & Varvel, N. H. (2023) · Scientific Reports · doi:10.1038/s41598-023-32752-9 · Cited by 18 · see citing works
Low-Level Primary Blast Induces Neuroinflammation and Neurodegeneration in Rats.
Li, Y., Yang, Z., Liu, B., Valdez, C., Chavko, M., & Cancio, L. (2019) · Military Medicine · doi:10.1093/milmed/usy330 · Cited by 18 · see citing works
Met/HGFR triggers detrimental reactive microglia in TBI
Rehman, R., Miller, M., Krishnamurthy, S. S., Kjell, J., Elsayed, L., Hauck, S. M., Heuvel, F. O., Conquest, A., Chandrasekar, A., Ludolph, A. C., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111867 · Cited by 23 · see citing works
Traumatic Brain Injury and Immunological Outcomes: the double-edged Killer
Datta, S., Lin, F., Jones, L., Pingle, S. C., Kesari, S., & Ashili, S. (2023) · Future Science OA · doi:10.2144/fsoa-2023-0037 · Cited by 15 · see citing works
“However, studies on the mice model suggested the dichotomous role of the chemokine receptor in regulating monocyte infiltration, tau protein phosphorylation, and further axonal damage [64].”
BackgroundRepetitive injury and absence of monocytes promote astrocyte self‐renewal and neurological recovery
Canhos, L. L., Chen, M., Falk, S., Popper, B., Straub, T., Götz, M., & Sirko, S. (2020) · Glia · doi:10.1002/glia.23893 · Cited by 18 · see citing works
“…with previous studies demonstrating that blocking of monocyte infiltration by CCR2 inhibition or knockout can prevent spatial memory deficits and improve cognitive functions in different experimental models of TBI (Gyoneva et al., 2015; Hsieh et al., 2014; Liu et al., 2017; Morganti et al., 2015).”
Genetic Contributions to Recovery following Brain Trauma: A Narrative Review.
Lakshmipathy, D., Rangarajan, S., Barreau, A., Lu, J., Kleinberg, G., & Lucke-Wold, B. (2024) · Frontiers in Bioscience · doi:10.31083/j.fbl2903103 · Cited by 13 · see citing works
“[77] showed that impairing Ccr2 could also have deleterious effects.”
BackgroundMir, P. A., Kumar, N. G., Bhutia, G. T., Chaudhary, P., Kaur, G., & Gupta, S. K. (2026) · GeroScience · doi:10.1007/s11357-025-02062-1 · Cited by 13 · see citing works
Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis
Kalinin, S., Meares, G. P., Lin, S. X., Pietruczyk, E. A., Saher, G., Spieth, L., Nave, K., Boullerne, A. I., Lutz, S. E., Benveniste, E. N., et al. (2019) · Glia · doi:10.1002/glia.23742 · Cited by 13 · see citing works
“Increased IgG accumulation may also reflect increased IgG leakage across the BBB, and several factors produced by astrocytes that can cause BBB damage were increased in het-cKO mice compared to WT mice, including CCL5 (Patabendige et al., 2018) and CCL2 (Gyoneva et al., 2015; Wang et al., 2014).”
BackgroundKhan, R. I., Nirzhor, S. S. R., & Rashid, B. (2018) · Brain Sciences · doi:10.3390/brainsci8090162 · Cited by 12 · see citing works
“Interestingly, the role of circulation monocytes in AD remains a highly debated issue since most the investigative experimental models included irradiation that compromised the blood-brain barrier [156].”
BackgroundThe role of the immune system during regeneration of the central nervous system
Sabin, K. Z., & Echeverri, K. (2019) · Journal of Immunology and Regenerative Medicine · doi:10.1016/j.regen.2019.100023 · Cited by 10 · see citing works
Baassiri, M. G. E., Raouf, Z., Jang, H., Scheese, D. J., Duess, J. W., Fulton, W. B., Sodhi, C. P., Hackam, D. J., & Nasr, I. W. (2024) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000004246 · Cited by 9 · see citing works
“35,36 In the context of the GI tract, the involvement of Ccr2 + monocytes has been elucidated in various intestinal disorders; however, their contribution to gut-associated outcomes following TBI has not been thoroughly examined.”
Katsumoto, A., Kokiko‐Cochran, O. N., Bemiller, S. M., Xu, G., Ransohoff, R. M., & Lamb, B. T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.978423 · Cited by 10 · see citing works
“Frontiers in Immunology 02 phosphorylation (3, 5, 7).”
BackgroundSelf-citationKii, N., Sawada, A., Yoshikawa, Y., Tachibana, S., & Yamakage, M. (2021) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000005699 · Cited by 11 · see citing works
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“Peripheral monocytes are known to enter the brain after traumatic brain injuries and seizures and contribute to neuronal injury and axonal damage (8, 9).”
BackgroundTaraschenko, O. D., Fox, H. S., Eldridge, E., Heliso, P., Al‐Saleem, F. H., Dessain, S. K., Casale, G. P., Willcockson, G., Anderson, K., Wang, W., et al. (2024) · Epilepsia · doi:10.1111/epi.17931 · Cited by 8 · see citing works
“42–44 In human monocyte cells, TLR4-dependent activation of CCL2 gene expression by lipopolysaccharide requires MyD88 recruitment and activation of NF-κ B1 transcription factors.”
BackgroundBaassiri, M. G. E., Chun, Y. H., Rahal, S. S., Fulton, W. B., Sodhi, C. P., Hackam, D. J., & Nasr, I. W. (2023) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000003858 · Cited by 10 · see citing works
“Moreover, a previous study by Gyoneva et al.33 also showed that infiltrating monocytes 374 Copyright © 2023 Wolters Kluwer H increased lesion cavity volume on PID 3.”
Falcone, J., Sohal, H. S., Kyriakides, T. R., & Bellamkonda, R. V. (2019) · Journal of Neural Engineering · doi:10.1088/1741-2552/ab1ef9 · Cited by 7 · see citing works
Sharma, R., Chu, E., Dill, L. K., Shad, A., Zamani, A., O'Brien, T., Casillas-Espinosa, P., Shultz, S., & Semple, B. (2022) · Journal of Neurotrauma · doi:10.1089/neu.2022.0033 · Cited by 5 · see citing works
“50 In contrast, Somebang and colleagues recently reported that Ccr2 gene deficiency in adult brain-injured mice triggered the alternative activation of different microglial phenotypes, suggesting an intimate relationship between resident and infiltrated immune cells.”
Immune-Based Therapies for Traumatic Brain Injury: Insights from Pre-Clinical Studies
Machado, C. A., Silva, A. C. S. E., de Miranda, A. S., Cordeiro, T. M. E., Ferreira, R. N., de Souza, L. C., Teixeira, A. L., & de Miranda, A. S. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867326666190710173234 · Cited by 5 · see citing works
Temporal and Spatial Patterns of Glial Activation After Unilateral Cortical Injury in Rats
Rich, K. K., Hjæresen, S., Andersen, M. S., Hansen, L. B., Mohammad, A. S., Gopinathan, N., Mogensen, T. C., Svenningsen, Å. F., & Zhang, M. (2026) · Life · doi:10.3390/life16010142 · Cited by 2 · see citing works
“Similar early ipsilateral CD11b increases have been reported in focal CCI and LFPI models [16,17,19,21], aligning with the robust but spatially restricted CD11b response observed in our focal aspiration model at day 3, which persisted through days 7–14 and became non-significant by day 21.”
Luo, Z.-H., Tong, C.-C., Cong, P.-F., Mao, S., Xu, Y., Hou, M., & Liu, Y.-N. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.110987 · Cited by 3
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“In mice, C-C chemokine motif receptor 2 (CCR2) deficiency has been shown to reduce monocyte infiltration, which is linked to AD-like pathology [31,62,64], and increase tau pathology [65].”
BackgroundShort-term behavioral and histological changes in a rodent model of mild traumatic brain injury
Clay, A., Carr, R., DuBien, J., & To, F. (2022) · Biomedical Engineering Advances · doi:10.1016/j.bea.2022.100061 · Cited by 1
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“CCL2 signaling through its receptor CCR2 helps regulate monocyte entry into the brain after TBI [225], and CCR2-associated macrophage responses are increased after injury [226–228].”
Zhang, R., Cao, L., Yong, W. V., Yang, L., & Xue, M.-Z. (2026) · Brain Hemorrhages · doi:10.1016/j.hest.2026.08.004
A Novel snoRNA, Gm24418 Attenuates Inflammation Injury After Acute TBI Through Regulating CCL2
Luo, M., Wang, Y., Guo, X.-H., Luo, W.-K., Yuan, Z., Yang, X.-P., Fan, X.-D., Yang, Z.-Y., & Tang, T. (2026) · Journal of Inflammation Research · doi:10.2147/jir.s583983
“38 41 The exploration of snoRNAs as diagnostic or prognostic biomarkers for TBI represents a promising research direction, given their specific expression changes and roles in post-transcriptional regulation.”
A Spatial Gene Expression Signature of the Mouse Brain Post-Injury at the Focal Point of Contusion
Kounelis-Wuillaume, S., Frank, A., Goguet, E., Alba, C., Sukumar, G., Wilkerson, M. D., Dalgard, C., McCabe, J. T., & Doughty, M. L. (2025) · Journal of Neurotrauma · doi:10.1177/08977151251390528
“24,81 While the role of Ccl2 in the recruitment of in fl ammatory Ccr2 + myeloid cells to the injured brain is established, 16,81 – 84 Ccl7 and Ccl12 can exert many of the same functions as Ccl2 by signaling through the same Ccr2 receptor.”
Victoroff, J. (2019) · Cambridge University Press eBooks · doi:10.1017/9781139696432.009
Pathological Tau as a Cause, and Consequence, of Cellular Dysfunction
Meier, S. E. (2019) · UKnowledge (University of Kentucky) · doi:10.13023/etd.2019.368
“ipsilateral and contralateral cortices [369].”
- Authors
- Gyoneva, S., Kim, D., Katsumoto, A., Kokiko-Cochran, O. N., Lamb, B. T., & Ransohoff, R. M.
- Affiliations
- Biogen (United States) (US)
- Cleveland Clinic (US)
- Corresponding author
- Gyoneva, Stefka
- Ransohoff, Richard M.
- Venue
- Journal of Neuroinflammation
- Published
- 2015-12
- Volume
- 12
- Issue
- 1
- Pages
- 228-228
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC4669659
- OpenAlex
- W2186638283
- Cited by
- 95
- References
- 49
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 9 · 2023: 6 · 2022: 12 · 2021: 3 · 2020: 13 · 2019: 12 · 2018: 15 · 2017: 11 · 2016: 4
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R21NS082798)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- CCR2, MCP-1, chemokine signaling, monocyte infiltration, traumatic brain injury, tau phosphorylation, axonal injury, microglial activation, neuroinflammation, chronic traumatic encephalopathy, Alzheimer's disease, lateral fluid percussion injury
- MeSH terms
- Animals, Brain Injuries, Female, Male, Monocytes, tau Proteins, Gene Deletion, Mice, Knockout, Mice, Receptors, CCR2
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