Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice
Open accessAbstract
An impaired ability to regulate microglia activation by fractalkine (CX3CL1) leads to microglia chronic sub-activation. How this condition affects outcome after acute brain injury is still debated, with studies showing contrasting results depending on the timing and the brain pathology. Here, we investigated the early and delayed consequences of fractalkine receptor (CX3CR1) deletion on neurological outcome and on the phenotypical features of the myeloid cells present in the lesions of mice with traumatic brain injury (TBI). Wild type (WT) and CX3CR1(-/-) C57Bl/6 mice were subjected to sham or controlled cortical impact brain injury. Outcome was assessed at 4 days and 5 weeks after TBI by neuroscore, neuronal count, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Compared with WT mice, CX3CR1(-/-) TBI mice showed a significant reduction of sensorimotor deficits and lower cellular damage in the injured cortex 4 days post-TBI. Conversely, at 5 weeks, they showed a worsening of sensorimotor deficits and pericontusional cell death. Microglia (M) and macrophage (μ) activation and polarization were assessed by quantitative immunohistochemistry for CD11b, CD68, Ym1, and inducible nitric oxide synthase (iNOS)-markers of M/μ activation, phagocytosis, M2, and M1 phenotypes, respectively. Morphological analysis revealed a decreased area and perimeter of CD11b(+) cells in CX3CR1(-/-) mice at 4 days post-TBI, whereas, at 5 weeks, both parameters were sig…
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CX3CR1 deficiency results in early protection but chronic worsening of CCI TBI-induced deficits due in part to a decrease in anti-inflammatory cytokines on CD11b+ sorted cells at 28 DPI.
“Subsequent work by a separate group confirms these results and demonstrates that CX3CR1 deficiency results in early protection but chronic worsening of CCI TBI-induced deficits due in part to a decrease in anti-inflammatory cytokines on CD11b+ sorted cells at 28 DPI (81).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [81]
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MethodSelf-citationThe immunological response to traumatic brain injury
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“Subsequent work by a separate group confirms these results and demonstrates that CX3CR1 deficiency results in early protection but chronic worsening of CCI TBI-induced deficits due in part to a decrease in anti-inflammatory cytokines on CD11b+ sorted cells at 28 DPI (81).”
ResultA Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI
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InfluentialSelf-citation<i>Cx3cr1-</i> deficient microglia exhibit a premature aging transcriptome
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Inflammation in Traumatic Brain Injury
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MethodProtection of Brain Injury by Amniotic Mesenchymal Stromal Cell-Secreted Metabolites
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“A concomitant reduction in the numbers of CD68 + cells along with reduced iNos and IL-1β gene expression in the cortices of injured CX3CR1 -/mice indicate a skewing of the acute lesion microenvironment towards a protective microglial phenotype (29,30) .”
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Mesenchymal stromal cell secretome for traumatic brain injury: Focus on immunomodulatory action
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“This interpretation is further supported by a study by Zanier and co-workers using a similar, yet slightly more severe model of CCI brain injury than that used in the Febinger study (Zanier et al., 2016).”
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MethodSelf-citationAgeing is associated with maladaptive immune response and worse outcome after traumatic brain injury
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“These initially activated cells are thought to provide acute protection of brain tissue within the first week after injury; while chronically, persistent glial activation is most often associated with neurodegeneration [38, 95, 96].”
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“, early protection but late worsening [43, 44].”
Microglial process convergence on axonal segments in health and disease
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“In support of this possibility are studies showing little or no effect of genetic microglial elimination or direct microglial inhibition using compounds targeting the CSF1 receptor in altering TBI-induced pathology([135,149,150]).”
BackgroundNeuro-Inflammation in Pediatric Traumatic Brain Injury—from Mechanisms to Inflammatory Networks
Fraunberger, E. A., & Esser, M. J. (2019) · Brain Sciences · doi:10.3390/brainsci9110319 · Cited by 33 · see citing works
“The converse can also occur, with microglia inducing a toxic astrocyte phenotype through secreting TNFα, IL-1β, and C1q [54] - CX3CR1 on microglia exhibits a time dependent effect on outcome after injury, playing a key role in inflammation (accumulation of leukocytes [55]), but is required for proper recovery in sever…”
BackgroundRole of MSK1 in the Induction of NF-κB by the Chemokine CX3CL1 in Microglial Cells
Galán-Ganga, M., García‐Yagüe, Á. J., & Lastres‐Becker, I. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00664-w · Cited by 30 · see citing works
Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury
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Autophagy & Phagocytosis in Neurological Disorders and their Possible Cross-talk
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“An increase in markers of autophagy has been reported in microglia after TBI, spinal cord injury(SCI), ischemic stroke and ICH in cellular and animal models [99-102].”
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Self-citationAtypical microglial response to biodiesel exhaust in healthy and hypertensive rats
Mumaw, C. L., Surace, M. J., Levesque, S., Kodavanti, U. P., Kodavanti, P. R. S., Royland, J. E., & Block, M. L. (2016) · NeuroToxicology · doi:10.1016/j.neuro.2016.10.012 · Cited by 22 · see citing works
“indicate that downregulation of CX3CR1 may have a more ominous consequence in chronic damage, as has been reported for neurotrauma (Zanier et al., 2015).”
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“This indicate that the CX3CL1-CX3CR1 signaling pathway plays varying roles at different time points [244].”
Revisiting the critical roles of reactive microglia in traumatic brain injury
Zhao, J., Zhou, Y., Zhou, C.-W., Zhan, K., Yang, M., Wen, M., & Zhu, L. (2025) · International Journal of Surgery · doi:10.1097/js9.0000000000002420 · Cited by 27 · see citing works
“Evidence suggests that, while microglia-mediated fractalkine receptor signaling is associated with early toxicity, it is also vital for later protective effects caused by TBI [ 394 ] .”
InfluentialGrossi, C., Artusi, C., Meroni, P., Borghi, M., Neglia, L., Lonati, P., Oggioni, M., Tedesco, F., Simoni, M. D., & Fumagalli, S. (2021) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1177/0271678x20984551 · Cited by 18 · see citing works
Cohen, E. M., Mohammed, S., Kavurma, M. M., Nedoboy, P. E., Cartland, S. P., Farnham, M. M. J., & Pilowsky, P. M. (2018) · Autonomic Neuroscience · doi:10.1016/j.autneu.2018.12.002 · Cited by 20 · see citing works
Menasria, R., Canivet, C., Piret, J., Gosselin, J., & Boivin, G. (2017) · Journal of General Virology · doi:10.1099/jgv.0.000667 · Cited by 17 · see citing works
“Indeed, the CX3CL1/CX3CR1 axis controls microglial effector functions and regulates their neurotoxic properties under inflammatory conditions in order to maintain a quiescent state [16, 20, 21].”
BackgroundWang, S., Weyer, M.-P., Hummel, R., Wilken‐Schmitz, A., Tegeder, I., & Schäfer, M. K. E. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03249-7 · Cited by 14 · see citing works
“CD68 is a phagolysosomal compartment marker, and its expression by microglia together with lipid droplet (LD) formation after TBI define the proinflammatory and phagocytic active state of microglia [48, 49].”
BackgroundSoliman, E., Mills, J., Ju, J., Kaloss, A. M., Basso, E. K. G., Groot, N. A., Kelly, C., Kowalski, E., Elhassanny, M., Chen, M. J., et al. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.747770 · Cited by 26 · see citing works
Ciechanowska, A., Ciapała, K., Pawlik, K., Oggioni, M., Mercurio, D., Simoni, M.-G. D., & Mika, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010045 · Cited by 21 · see citing works
Ciechanowska, A., Popiołek-Barczyk, K., Ciapała, K., Pawlik, K., Oggioni, M., Mercurio, D., Simoni, M. D., & Mika, J. (2020) · Pharmacological Reports · doi:10.1007/s43440-020-00187-y · Cited by 16 · see citing works
Pedragosa, J., Mercurio, D., Oggioni, M., Márquez-Kisinousky, L., Simoni, M. D., & Planas, A. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113865 · Cited by 15 · see citing works
Oggioni, M., Mercurio, D., Minuta, D., Fumagalli, S., Popiołek-Barczyk, K., Sironi, M., Ciechanowska, A., Ippati, S., Blasio, D. D., Perego, C., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-89032-7 · Cited by 14 · see citing works
Self-citationInampudi, C., Ciccotosto, G. D., Cappai, R., & Crack, P. J. (2020) · Journal of Neurotrauma · doi:10.1089/neu.2019.6955 · Cited by 12 · see citing works
“170 173 Whereas it is uncertain whether CX3CL1 or its receptor, CX3CR1, has a sex-dependent role in TBI.”
Machado, C. A., Oliveira, B. D. S., Dias, T. L., de Barros, J. L. V. M., Ferreira, G., Cordeiro, T., Feracin, V., Alexandre, C. H., Abreu, L. K. S., da Silva, W. N., et al. (2023) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2023.578242 · Cited by 12 · see citing works
Biomarker Associations in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage
Spantler, D., Molnár, T., Simon, D., Berki, T., Büki, A., Schwarcz, A., & Csécsei, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158789 · Cited by 12 · see citing works
“This protein may be involved in the inflammatory response to traumatic brain injury (TBI), particularly in the accumulation of leukocytes in the injured parenchyma [19].”
BackgroundCentripetal migration and prolonged retention of microglia promotes spinal cord injury repair
Ye, J., Shan, F., Xu, X.-Z., Liang, C., Zhang, N.-Y., Hu, H., Li, J., Ouyang, F., Wang, J.-W., Zhao, Y., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03411-9 · Cited by 11 · see citing works
“However, contrasting results emerge from other studies in traumatic brain injury and SCI, where using a CX3CR1 −/− mouse model confirms a beneficial function of this axis in microglia, assisting in neuronal preservation and promoting motor recovery [41, 42].”
Sapia, R. D., Rizzi, M., Moro, F., Lisi, I., Caccamo, A., Ravizza, T., Vezzani, A., & Zanier, E. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106251 · Cited by 11 · see citing works
Self-citationC. elegans detects toxicity of traumatic brain injury generated tau
Zanier, E. R., Barzago, M. M., Vegliante, G., Romeo, M., Restelli, E., Bertani, I., Natale, C., Colnaghi, L., Colombo, L., Russo, L., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105330 · Cited by 11 · see citing works
Self-citationThe 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
Wu, Y., Park, T., Kwon, E. E., Feng, S. X., Schweder, P. M., Dragunow, M., Shim, V., & Rosset, S. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.994251 · Cited by 9 · see citing works
“Various experimental models have already been developed, including in vivo animal models, and in vitro models with cultured animal and human brain cells, where the majority of studies used animal cells (Arun et al., 2011; Febinger et al., 2015; Ravin et al., 2016; Sherman et al., 2016; Zanier et al., 2016).”
BackgroundThe role of interleukin-17 in epilepsy
An, J., Li, H., Xia, D., Xu, B., Wang, J., Qiu, H., & He, J. (2022) · Epilepsy Research · doi:10.1016/j.eplepsyres.2022.107001 · Cited by 9 · see citing works
Wen, J., & Huang, C.-X. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.7536 · Cited by 7 · see citing works
“whereas soluble FKN is generated via cleavage at the base of the mucin-like stalk by two metalloproteinases, a disintegrin and metalloproteinase (ADAM) 10 and ADAM17 (12-14).”
BackgroundKay, T. V., Price, A. L., Sprenger, M., Radosova, V. J., Thompson, A., Martin, E. L., Dunn, D., Popov, V., Mikhailov, S., Reitman, Z., et al. (2025) · International Journal of Radiation Oncology, Biology, Physics · doi:10.1016/j.ijrobp.2025.09.057 · Cited by 2
Machado, C. A., Oliveira, B. D. S., Fernandes, H. D. B., de Carvalho, R. T., Pozzolin, E. T., Kangussu, L., Carvalho, B., Teixeira, A. L., & de Miranda, A. D. (2025) · Molecular and cellular neurosciences · doi:10.1016/j.mcn.2025.104013 · Cited by 1 · see citing works
Role of misfolded tau in the onset and progression of brain toxicity after traumaPreprint
Zanier, E., Barzago, M. M., Vegliante, G., Romeo, M., Bertani, I., Natale, C., Colnaghi, L., Colombo, L., Russo, L., Micotti, E., et al. (2020) · bioRxiv · doi:10.1101/2020.06.18.159301 · Cited by 1 · see citing works
Self-citationTemporal Dynamics of Neuroinflammation after Cortical Injury in Mice
Manzhulo, I., Tyrtyshnaia, A. A., Avgustinovich, F. K., Manzhulo, O. S., Gromova, E., & Ivashkevich, D. (2025) · Neurochemical Journal · doi:10.1134/s1819712425700862
Role of chemokines in depression: Highlights on CX3CL1/CX3CR1 signaling
Yin, Y.-Y., & Li, Y.-F. (2025) · Journal of Psychopharmacology · doi:10.1177/02698811251389532
“…through CX 3 CL1/CX 3 CR1 signaling to help clear debris, release cytokines, and repair tissue (Dorfman et al., 2017; Liu et al., 2015); on the other hand, neurons inhibit the microglial activation through CX 3 CL1/CX 3 CR1 signaling once the inflammation is excessive (Zanier et al., 2016).”
Hu, S.-C. (2015) · doi:10.70675/10c4a5a4zd286z4fbcz9a30z00a55e9e0842
“plus importante des cellules CD11b+ au niveau de la lésion (Zanier et al., 2015).”
Background
- Authors
- Zanier, E. R., Marchesi, F., Ortolano, F., Perego, C., Arabian, M., Zoerle, T., Sammali, E., Pischiutta, F., & De Simoni, M.-G.
- Affiliations
- Mario Negri Institute for Pharmacological Research (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Department of Neuroscience, IRCCS-Istituto di Recerche Farmacologiche Mario Negri, Milan, Italy.
- Corresponding author
- Zanier, Elisa R.
- ORCID
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2016-06
- Volume
- 33
- Issue
- 11
- Pages
- 1060-1072
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC4892197
- OpenAlex
- W2404046606
- Cited by
- 94
- References
- 0
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 6 · 2023: 4 · 2022: 9 · 2021: 15 · 2020: 15 · 2019: 9 · 2018: 11 · 2017: 7 · 2016: 9
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Neurotrauma (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- CX3CR1, fractalkine, traumatic brain injury, microglial activation, myeloid cell polarization, M1/M2 macrophages, sensorimotor deficits, IL-10, insulin-like growth factor I, neuroinflammation, controlled cortical impact injury, neuroprotection
- MeSH terms
- Brain Injuries, Traumatic, CX3C Chemokine Receptor 1, Animals, Disease Models, Animal, Macrophage Activation, Mice, Inbred C57BL, Time Factors, Microglia, Mice, Knockout, Disease Progression, Mice, Protective Factors
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