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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CCX872 and RS504393, two selective CCR2 antagonists, reduce post-injury macrophage recruitment and improve functional recovery after CCI and weight drop TBI.
“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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“phages can contribute to neuroinflammation after TBI (Hsieh et al., 2014; Israelsson et al., 2014; Morganti et al., 2015; Semple et al., 2010), with a marked accumulation of inflammatory macrophages (CD11bCD45, CCR2F4/80) in injured cortex within 24 h (Hsieh et al.”
InfluentialGreenhalgh, A. D., Zarruk, J. G., Healy, L. M., Jesudasan, S. J. B., Jhelum, P., Salmon, C. K., Formanek, A., Russo, M. V., Antel, J. P., McGavern, D. B., et al. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2005264 · Cited by 212 · see citing works
“Compression injury and intravital two-photon microscopy For mTBI experiments, CX3CR1 gfp/+ mice were anesthetized with ketamine, xylazine, and acepromazine and maintained at a core temperature of 37 ºC.”
BackgroundInfluentialHennessy, E., Griffin, É. W., & Cunningham, C. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2745-14.2015 · Cited by 178 · see citing works
“…in TBI and stroke (Semple et al., 2010; Ritter et al., 2011) and limiting neutrophil and CCR2 macrophage infiltration improves neuropathological and functional outcomes in models of cerebral ischemia, TBI, and repeated concussion (McColl et al., 2008; Shultz et al., 2013; Morganti et al., 2015).”
BackgroundAndonegui, G., Zelinski, E. L., Schubert, C. L., Knight, D., Craig, L. A., Winston, B. W., Spanswick, S. C., Petri, B., Jenne, C. N., Sutherland, J., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.99364 · Cited by 177 · see citing works
Ritzel, R. M., Doran, S. J., Glaser, E. P., Meadows, V. E., Faden, A. I., Stoica, B. A., & Loane, D. J. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.02.010 · Cited by 156 · see citing works
Patel, N. A., Moss, L. D., Lee, J.-Y., Tajiri, N., Acosta, S., Hudson, C., Parag, S., Cooper, D. R., Borlongan, C. V., & Bickford, P. C. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1240-3 · Cited by 175 · see citing works
Doran, S. J., Ritzel, R., Glaser, E. P., Henry, R., Faden, A., & Loane, D. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.6019 · Cited by 154 · see citing works
“Pre-clinical studies that have compared male and female animals report mixed and unclear re- sults with regard to effects of biological sex on secondary injury mechanisms and TBI outcomes.13–21 Microglia and infiltrating myeloid cells (inflammatory monocytes and neutrophils) play central roles in acute neuroinflammato…”
BackgroundInfluentialHegdekar, N., Sarkar, C., Bustos, S., Ritzel, R. M., Hanscom, M., Ravishankar, P., Philkana, D., Wu, J., Loane, D. J., & Lipinski, M. M. (2023) · Autophagy · doi:10.1080/15548627.2023.2167689 · Cited by 158 · see citing works
“The immune cells participating in TBI neuroinflammatory responses include both activated resident microglia and infiltrating monocytes/macrophages [8,31].”
BackgroundMethodInfluentialDissemination of brain inflammation in traumatic brain injury
Shi, K., Zhang, J., Dong, J., & Shi, F. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0213-5 · Cited by 181 · see citing works
Brain trauma elicits non-canonical macrophage activation states
Kim, C. C., Nakamura, M. C., & Hsieh, C. L. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0581-z · Cited by 149 · see citing works
“In fact, studies have identified Ccr2 as a potential target to improve the functional outcomes of TBI [5, 7, 21, 31].”
BackgroundRusso, M. V., Latour, L. L., & McGavern, D. B. (2018) · Nature Immunology · doi:10.1038/s41590-018-0086-2 · Cited by 149 · see citing works
Miró‐Mur, F., Pérez-de-Puig, I., Ferrer-Ferrer, M., Urra, X., Justicia, C., Chamorro, Á., & Planas, A. M. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.08.010 · Cited by 133 · see citing works
“, 2014), and following traumatic brain injury (Hsieh et al., 2014; Morganti et al., 2015).”
BackgroundThe immunological response to traumatic brain injury
Needham, E., Helmy, A. E., Zanier, E. R., Jones, J., Coles, A. J., & Menon, D. K. (2019) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2019.04.005 · Cited by 155 · see citing works
The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
Kokiko-Cochran, O. N., & Godbout, J. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00672 · Cited by 128 · see citing works
“Use of CX3CR1GFP/+CCR2RFP/+ reporter mice provides insight into the role of microglia and macrophages following TBI (76); however, it is still unclear if myeloid cells associated with chronic injury lesions are CX3CR1+ microglia or a mixture of CX3CR1+ microglia and CX3CR1+ peripheral macrophages that downregulated CC…”
BackgroundMethodTargeting innate immunity for neurodegenerative disorders of the central nervous system
Andreasson, K. I., Bachstetter, A. D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D. C., Low, D., Lynch, M. A., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13667 · Cited by 126 · see citing works
Krukowski, K., Chou, A., Feng, X., Tiret, B., Paladini, M. S., Riparip, L., Chaumeil, M. M., Lemere, C. A., & Rosi, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123753 · Cited by 139 · see citing works
“Previous work from our group and others identified the critical role that peripheral macrophage infiltration into the brain, as well as microglia activation, plays in TBI-related cognitive deficits [7,8,30].”
BackgroundSelf-citationNeurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia
Wang, P., Velagapudi, R., Kong, C., Rodriguiz, R. M., Wetsel, W. C., Yang, T., Berger, M., Gelbard, H. A., Colton, C. A., & Terrando, N. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12064 · Cited by 118 · see citing works
Cross‐talk between monocyte invasion and astrocyte proliferation regulates scarring in brain injury
Frik, J., Merl‐Pham, J., Plesnila, N., Mattugini, N., Kjell, J., Kraska, J., Gomez, R. M., Hauck, S. M., Sirko, S., & Götz, M. (2018) · EMBO Reports · doi:10.15252/embr.201745294 · Cited by 126 · see citing works
“Moreover, CCR2 + monocytes were identified as the main source of Nox2-mediated neurotoxic ROS after TBI [21], a role similar to some results obtained in spinal cord injury [70].”
InfluentialThe neuroprotective effect of dexmedetomidine and its mechanism
Hu, Y.-J., Zhou, H., Zhang, H.-X., Sui, Y., Zhang, Z., Zou, Y., Li, K., Zhao, Y., Xie, J., & Zhang, L.-Z. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.965661 · Cited by 110 · see citing works
“4MCP1-CCR2 can promote macrophage aggregation, aggravate inflammatory responses and even cause cognitive impairment(Morganti et al., 2015).”
BackgroundTime-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury
Febinger, H. Y., Thomasy, H. E., Pavlova, M. N., Ringgold, K. M., Barf, P. R., George, A. M., Grillo, J. N., Bachstetter, A. D., Garcia, J. A., Cardona, A. E., et al. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0386-5 · Cited by 110 · see citing works
“[50] using CX3CR1 CCR2 reporter mice have demonstrated a broad spectrum of M1-M2 polarization mRNA gene expression following TBI, with changes occurring primarily during the first 48 h.”
Xing, Z., Xia, Z., Peng, W., Li, J., Zhang, C., Fu, C., Tang, T., Luo, J., Zou, Y., Fan, R., et al. (2016) · Scientific Reports · doi:10.1038/srep20040 · Cited by 100 · see citing works
Inflammation in Traumatic Brain Injury
Postolache, T. T., Wadhawan, A., Can, A., Lowry, C. A., Woodbury, M., Makkar, H., Hoisington, A. J., Scott, A. J., Potocki, E., Benros, M. E., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-191150 · Cited by 150 · see citing works
Macrophagic and microglial complexity after neuronal injury
Mesquida-Veny, F., del Rı́o, J. A., & Hervera, A. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101970 · Cited by 104 · see citing works
Acute drivers of neuroinflammation in traumatic brain injury
Wofford, K. L., Loane, D. J., & Cullen, D. K. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.255958 · Cited by 103 · see citing works
“Most data suggest that peripheral macrophages contribute to secondary injury pathology by homing to the site of injury and amplifying inflammation (Hsieh et al., 2014; Morganti et al., 2015).”
Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury
Gyoneva, S., Kim, D., Katsumoto, A., Kokiko-Cochran, O. N., Lamb, B. T., & Ransohoff, R. M. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0443-0 · Cited by 95 · see citing works
“studies [23, 30], deletion of Ccr2 prevented the infiltration”
BackgroundKrukowski, K., Feng, X., Paladini, M. S., Chou, A., Sacramento, K., Grue, K., Riparip, L.-K., Jones, T., Campbell-Beachler, M., Nelson, G., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-26039-7 · Cited by 92 · see citing works
Self-citationEffects of Microglial Activation and Polarization on Brain Injury After Stroke
Dong, R., Huang, R., Wang, J., Liu, H., & Xu, Z. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.620948 · Cited by 87 · see citing works
Therapies negating neuroinflammation after brain trauma
Hellewell, S. C., Semple, B. D., & Morganti-Kossmann, M. C. (2015) · Brain Research · doi:10.1016/j.brainres.2015.12.024 · Cited by 92 · see citing works
Cecal Ligation and Puncture Results in Long-Term Central Nervous System Myeloid Inflammation
Singer, B. H., Newstead, M. W., Zeng, X., Cooke, C. L., Thompson, R. C., Singer, K., Ghantasala, R., Parent, J. M., Murphy, G. G., Iwashyna, T. J., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149136 · Cited by 96 · see citing works
Saber, M., Kokiko‐Cochran, O. N., Puntambekar, S. S., Lathia, J. D., & Lamb, B. T. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4401 · Cited by 95 · see citing works
“65 Another study showed that impairing macrophage infiltration using CCR2 deficient mice is beneficial for TBI recovery and cognitive outcome after TBI.”
Dash, P. K., Zhao, J., Kobori, N., Redell, J. B., Hylin, M. J., Hood, K. N., & Moore, A. N. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.3197-15.2016 · Cited by 93 · see citing works
“, 2008), we also examined the expression of C-C chemokine receptor type 2 (CCR2), as this receptor is expressed only by circulating monocytes/ macrophages and not by resident microglia (Morganti et al., 2015).”
BackgroundResolution of neuroinflammation: mechanisms and potential therapeutic option
Dokalis, N., & Prinz, M. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00764-1 · Cited by 87 · see citing works
Plasma dilution improves cognition and attenuates neuroinflammation in old mice
Mehdipour, M., Mehdipour, T., Skinner, C. M., Wong, N., Liu, C., Chen, C.-C., Jeon, O. H., Zuo, Y., Conboy, M. J., & Conboy, I. M. (2020) · GeroScience · doi:10.1007/s11357-020-00297-8 · Cited by 83 · see citing works
Henry, R. J., Doran, S. J., Barrett, J. P., Meadows, V. E., Sabirzhanov, B. E., Stoica, B. A., Loane, D. J., & Faden, A. I. (2018) · Neurotherapeutics · doi:10.1007/s13311-018-0665-9 · Cited by 82 · see citing works
“Morganti and colleagues [47] recently demonstrated that inhibition of CCL2–CCR2 signaling following TBI, using a selective CCR2 antagonist, attenuated pro-inflammatory signaling.”
BackgroundThe immune system in traumatic brain injury
Plesnila, N. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.10.008 · Cited by 80 · see citing works
Understanding Immune‐Driven Brain Aging by Human Brain Organoid Microphysiological Analysis Platform
Ao, Z., Song, S., Tian, C., Cai, H., Li, X., Miao, Y., Wu, Z., Krzesniak, J., Ning, B., Gu, M., et al. (2022) · Advanced Science · doi:10.1002/advs.202200475 · Cited by 77 · see citing works
Chen, H., Chen, C., Kuo, Y.-M., Chen, B., Kuan, I. S., Huang, H., Lee, J., Anthony, N. R., Kuan, C.-Y., & Sun, Y. (2021) · Theranostics · doi:10.7150/thno.64033 · Cited by 90 · see citing works
“Elucidating these issues has implications for both basic science and clinical practice, since the influx of monocytes may be impeded by targeting the MCP1-CCR2 chemo-attraction axis as shown in several past studies [17-19 , 43-46”
ResultMacrophage depletion reduced brain injury following middle cerebral artery occlusion in mice
Ma, Y., Li, Y.-N., Jiang, L., Wang, L.-P., Jiang, Z., Wang, Y.-T., Zhang, Z., & Yang, G.-Y. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0504-z · Cited by 77 · see citing works
“Both peripheral infiltrated macrophages and brain resident microglia activation were implicated in demyelinationassociated diseases such as globoid cell leukodystrophy, multiple sclerosis, spinal cord injury, and traumatic brain injury [28–31].”
BackgroundGuglielmetti, C., Le Blon, D., Santermans, E., Salas-Perdomo, A., Daans, J., De Vocht, N., Shah, D., Hoornaert, C., Praet, J., Peerlings, J., et al. (2016) · Glia · doi:10.1002/glia.23053 · Cited by 76 · see citing works
“Furthermore, in the past years, numerous studies have reported the beneficial effect operated by the shift from M1to M2-polarized immune cells in other preclinical models of MS and other models of neuroinflammation (Cash et al., 1994; Janssens et al,. 2015; Liu et al., 2013; Miro-Mur et al., 2016; Miron et al., 2013;…”
BackgroundKrukowski, K., Nolan, A., Becker, M., Picard, K., Vernoux, N., Frias, E. S., Feng, X., Tremblay, M., & Rosi, S. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.08.210 · Cited by 86 · see citing works
“While acutely microglia contribute to restoring homeostasis after the injury, persistently reactive microglia produce pro-inflammatory/cytotoxic molecules contributing to neuronal damage (18-20).”
BackgroundSelf-citationAge exacerbates the CCR2/5-mediated neuroinflammatory response to traumatic brain injury
Morganti, J. M., Riparip, L., Chou, A., Liu, S., Gupta, N. M., & Rosi, S. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0547-1 · Cited by 84 · see citing works
“These data align with our previous work implicating CCR2 macrophages as the predominant source for NOX2 gene expression following TBI [13].”
BackgroundMethodResultInfluentialSelf-citationMacrophages play an essential role in trauma-induced sterile inflammation and tissue repair
Peiseler, M., & Kubes, P. (2018) · European Journal of Trauma and Emergency Surgery · doi:10.1007/s00068-018-0956-1 · Cited by 77 · see citing works
Puntambekar, S. S., Saber, M., Lamb, B. T., & Kokiko‐Cochran, O. N. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.03.033 · Cited by 78 · see citing works
“kinetics of the macrophage response following TBI (22) .”
BackgroundInfluentialChou, A., Krukowski, K., Morganti, J. M., Riparip, L., & Rosi, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061616 · Cited by 78 · see citing works
“The prevention of CCR2+ monocyte infiltration in young animals significantly reduces both proand anti-inflammatory markers and ultimately improves cognitive outcomes after TBI [17,18].”
BackgroundMethodResultInfluentialSelf-citationParillaud, V. R., Lornet, G., Monnet, Y., Privat, A., Haddad, A. T., Brochard, V., Bekaert, A., de Chanville, C. B., Hirsch, E., Combadière, C., et al. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0830-9 · Cited by 68 · see citing works
“, in traumatic brain injury models [41, 42], they are protective in motor neuron disease ALS mice [43].”
BackgroundCCR2 deficiency alters activation of microglia subsets in traumatic brain injury
Somebang, K., Rudolph, J. D., Imhof, I., Li, L., Niemi, E. C., Shigenaga, J. K., Tran, H., Gill, T. M., Lo, I., Zabel, B. A., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109727 · Cited by 74 · see citing works
“, 2018), CCX872, improved TBI outcomes in WT mice (Morganti et al., 2015) when it is administered prior to trauma.”
BackgroundResultMicroglia Receptors in Animal Models of Traumatic Brain Injury
Younger, D., Murugan, M., Rao, K. V. R., Wu, L., & Chandra, N. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1428-7 · Cited by 69 · see citing works
Moss, L. D., Sode, D., Patel, R. S., Lui, A., Hudson, C., Patel, N. A., & Bickford, P. C. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105173 · Cited by 63 · see citing works
“Prevention of aspects of the secondary inflammatory response have been shown to modulate recovery (Bachstetter et al., 2015, 2016; Morganti et al., 2015, 2019; Chou et al., 2018; Rowe et al., 2018).”
BackgroundKäufer, C., Chhatbar, C., Bröer, S., Waltl, I., Ghita, L., Gerhauser, I., Kalinke, U., & Löscher, W. (2018) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1806754115 · Cited by 61 · see citing works
“CCR2 antagonists are efficacious after traumatic brain injury (47) and have entered clinical trials for the treatment of neuropathic pain (48).”
BackgroundChen, H., Ji, H., Zhang, M., Liu, Z., Lao, L.-F., Deng, C., Chen, J.-W., & Zhong, G.-B. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3046-16.2017 · Cited by 60 · see citing works
“Hsieh et al. (2014), Ka et al. (2015), and Morganti et al. (2015) reported that increased CCR2 expression may directly trigger the recruitment of macrophages to the CNS and that decreased expression impaired macrophage infiltration into the CNS.”
BackgroundWangler, L. M., & Godbout, J. P. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.08.008 · Cited by 59 · see citing works
Deletion of p38α MAPK in microglia blunts trauma-induced inflammatory responses in mice
Morganti, J. M., Goulding, D. S., & Eldik, L. J. V. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1493-5 · Cited by 58 · see citing works
Self-citationTraumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment
Delage, C., Taib, T., Mamma, C., Lerouet, D., & Besson, V. C. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13101624 · Cited by 67 · see citing works
“Following TBI, inhibition of monocyte/macrophage infiltration in aged mice prevents spatial memory deficits [203] to a greater extent than in young adult mice [104].”
BackgroundPopiołek-Barczyk, K., Ciechanowska, A., Ciapała, K., Pawlik, K., Oggioni, M., Mercurio, D., Simoni, M. G. D., & Mika, J. (2020) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2020.101671 · Cited by 70 · see citing works
Abe, N., Choudhury, M. E., Watanabe, M., Kawasaki, S., Nishihara, T., Yano, H., Matsumoto, S., Kunieda, T., Kumon, Y., Yorozuya, T., et al. (2018) · Glia · doi:10.1002/glia.23469 · Cited by 57 · see citing works
Minogue, A. (2017) · Progress in Neuro-psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.02.008 · Cited by 56 · see citing works
“cesses required to limit tissue damage (Kapellos et al., 2016; Kumar et al., 2015, 2016; Morganti et al., 2015).”
InfluentialEffects of advanced age upon astrocyte-specific responses to acute traumatic brain injury in mice
Early, A. N., Gorman, A. A., Eldik, L. J. V., Bachstetter, A. D., & Morganti, J. M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01800-w · Cited by 63 · see citing works
“17 multivariate methods to delineate the effect of injury and time [32].”
BackgroundMethodSelf-citationIn vivo metabolic imaging of Traumatic Brain Injury
Guglielmetti, C., Chou, A., Krukowski, K., Najac, C., Feng, X., Riparip, L., Rosi, S., & Chaumeil, M. M. (2017) · Scientific Reports · doi:10.1038/s41598-017-17758-4 · Cited by 52 · see citing works
Self-citationYang, H.-C., Zhang, M., Wu, R., Zheng, H.-Q., Zhang, L.-Y., Luo, J., Li, L., & Hu, X.-Q. (2020) · World Journal of Stem Cells · doi:10.4252/wjsc.v12.i2.152 · Cited by 51 · see citing works
STAT6 mediates the effect of ethanol on neuroinflammatory response in TBI.
Heuvel, F. O., Holl, S., Chandrasekar, A., Li, Z.-H., Wang, Y.-B., Rehman, R., Förstner, P., Sinske, D., Palmer, A., Wiesner, D., et al. (2019) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2019.06.019 · Cited by 51 · see citing works
Interleukin-6 in Traumatic Brain Injury: A Janus-Faced Player in Damage and Repair
Ciryam, P., Gerzanich, V., & Simard, J. M. (2023) · Journal of Neurotrauma · doi:10.1089/neu.2023.0135 · Cited by 54 · see citing works
“226 Using flow cytometry, Li and colleagues sought to identify IL-6 expression in specific cell types in the brains of mice subjected to CCI.”
Garnett, C. N., Watson, J. B., Higgins, E. K., Quan, N., & Bachstetter, A. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.688254 · Cited by 60 · see citing works
Castranio, E. L., Mounier, A., Wolfe, C. M., Nam, K. N., Fitz, N. F., Letronne, F., Schug, J., Koldamova, R. P., & Lefterov, I. M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.05.006 · Cited by 55 · see citing works
“Studies have shown that the expression levels of themajority of those inflammatory factors are associated with severity of injury and outcome in TBI patients, the reduction of neurobehavioral impairments and injury volume as well as the survival rates in rodent models (Morganti et al., 2015; Yang et al., 2013).”
BackgroundRotterman, T. M., Akhter, E. T., Lane, A. R., MacPherson, K. P., García, V. V., Tansey, M. G., & Álvarez, F. J. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.2945-17.2019 · Cited by 50 · see citing works
“…models (Ajami et al., 2011; Prinz et al., 2011; Shi and Pamer, 2011), after spinal cord injury (Donnelly et al., 2011; Evans et al., 2014) and after traumatic brain injury (Morganti et al., 2015; Katsumoto et al., 2018), and to study dorsal horn pain mechanisms after PNI (Gu et al., 2016).”
BackgroundZhao, Y., Mu, H., Huang, Y., Li, S., Wang, Y., Stetler, R. A., Bennett, M. V. L., Dixon, C. E., Chen, J., & Shi, Y. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02563-2 · Cited by 47 · see citing works
“Since CX3CR1 is expressed by microglia and peripheral monocytes [17], and both cells are present in the brain after TBI [29], we employed a tamoxifen pulse knockout strategy to restrict CX3CR1CreER-mediated HDAC3 knockout to microglia [17].”
BackgroundDean, T., Mendiola, A. S., Yan, Z., Meza-Acevedo, R., Cabriga, B., Akassoglou, K., & Ryu, J. K. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03092-w · Cited by 53 · see citing works
“These sequelae are likely responsible for TBI-induced oxidative damage and cortical loss observed in our study, and provides an underlying mechanism triggering monocyte and microglia post-TBI neurotoxicity [16, 46–49].”
BackgroundMethodLinks between Thrombosis and Inflammation in Traumatic Brain Injury
Hubbard, W. B., Dong, J.-F., Crúz, M., & Rumbaut, R. (2020) · Thrombosis Research · doi:10.1016/j.thromres.2020.10.041 · Cited by 47 · see citing works
Enam, S. F., Kader, S. R., Bodkin, N., Lyon, J. G., Calhoun, M. A., Azrak, C., Tiwari, P. M., Vanover, D. A., Wang, H., Santangelo, P. J., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01860-y · Cited by 55 · see citing works
Yellowhair, T. R., Noor, S., Maxwell, J. R., Anstine, C. V., Oppong, A. Y., Robinson, S., Milligan, E. D., & Jantzie, L. L. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.11.002 · Cited by 57 · see citing works
“Notably, limiting neutrophils and macrophages improves neuropathological and functional outcomes following stroke and TBI (Semple et al., 2010; Morganti et al., 2015),”
BackgroundBlon, D. L., Guglielmetti, C., Hoornaert, C., Quarta, A., Daans, J., Dooley, D., Lemmens, E., Praet, J., Vocht, N. D., Reekmans, K., et al. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0756-7 · Cited by 52 · see citing works
“Although microglia and CNS-invading peripheral monocytes both act as phagocytic cells of the brain, it is currently becoming accepted that these two cell types are more distinct than generally assumed [2, 5].”
BackgroundSaber, M., Giordano, K. R., Hur, Y., Ortiz, J. B., Morrison, H., Godbout, J. P., Murphy, S. M., Lifshitz, J., & Rowe, R. K. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14611 · Cited by 46 · see citing works
“In male mice or mixed sex studies, monocyte-derived macrophages have increased in the brain after TBI, as have peripheral monocytes and neutrophils in the blood long-term (Morganti et al., 2015; Ritzel et al., 2018; Saber et al., 2016; Schwulst et al., 2013).”
BackgroundInfluentialWang, Y., Xiao, L., Lu, J., Hernigou, P., & Jin, F. (2024) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1366398 · Cited by 42 · see citing works
Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System
Ivan, D. C., Walthert, S., Berve, K., Steudler, J., & Locatelli, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.609921 · Cited by 53 · see citing works
The Immune System's Role in the Consequences of Mild Traumatic Brain Injury (Concussion)
Verboon, L. N., Patel, H. C., & Greenhalgh, A. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.620698 · Cited by 58 · see citing works
Lee, S., Mattingly, A. J., Lin, A., Sacramento, J. A., Mannent, L., Castel, M., Canolle, B., Delbary-Gossart, S., Ferzaz, B., Morganti, J. M., et al. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0544-4 · Cited by 55 · see citing works
“transgenic is a heterozygous mouse with bi-allelic expression of RFP and CCR2 [20, 50].”
BackgroundInfluentialSelf-citationMorioka, K., Marmor, Y., Sacramento, J., Lin, A., Shao, T., Miclau, K., Clark, D., Beattie, M., Marcucio, R., Miclau, T., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-48126-z · Cited by 43 · see citing works
Self-citationEvidence of a distinct peripheral inflammatory profile in sport-related concussion
Battista, A. P. D., Churchill, N. W., Rhind, S. G., Richards, D. W., & Hutchison, M. G. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1402-y · Cited by 51 · see citing works
Haar, C. V., Lam, F. C. W., Adams, W. K., Riparip, L., Kaur, S., Muthukrishna, M., Rosi, S., & Winstanley, C. A. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00166 · Cited by 45 · see citing works
Self-citation
- 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 › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › 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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