Transcranial amelioration of inflammation and cell death after brain injury.
Open accessAbstract
Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function. At present, no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain insights into TBI pathogenesis, we developed a novel murine closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic-receptor-dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We also show that the skull bone is permeable to small-molecular-weight compounds, and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results shed light on the acute cellular response to TBI and provide a means to locally deliver therapeutic compounds to the site of injury.
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In a mild closed-skull compression injury model, Cx3cr1+ meningeal macrophages die within 30 min of injury induction, leading to formation of a honeycomb network of microglia at the glial limitans that likely prevents the spread of reactive oxygen species from the leptomeninges into the brain parenchyma.
“Cx3cr1+ meningeal macrophages are observed dying within 30 min of injury induction, leading to formation of a “honeycomb” network of microglia at the glial limitans, likely preventing the spread of reactive oxygen species from the leptomeninges into the brain parenchyma”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Roth et al., 2013
Damage to the glia limitans superficialis after TBI results in a profound morphological transformation of underlying microglia that depends on ATP release by surface-associated astrocytes and subsequent detection by microglial purinergic receptors.
“For example, damage to the glia limitans superficialis after TBI results in a profound morphological transformation of the underlying microglia that depends on ATP release by surface-associated astrocytes and subsequent detection by microglial purinergic receptors (126).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [126]
Microglia transform into honeycomb- and jellyfish-like morphologies that provide barrier support and debris clearance.
“Real-time imaging studies revealed that microglia transform into honeycomb- and jellyfish-like morphologies that provide barrier support and debris clearance (126).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [126]
TBI can disrupt vascular integrity in the meninges and brain parenchyma, resulting in leakage of materials from the blood supply into CNS.
“TBI can disrupt vascular integrity in the meninges and brain parenchyma, resulting in leakage of materials from the blood supply into CNS (Fig. 4) (125-127).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [126]
In the absence of this microglial transformation, the glia limitans leaked profoundly.
“In the absence of this transformation, the glia limitans leaked profoundly.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [126]
In the minutes following TBI, microglia are recruited via purinergic signaling to clear necrotic debris and adopt a phagocytic state.
“In the minutes following TBI, microglia are recruited via purinergic signaling to clear necrotic debris and adopt a phagocytic state [100,107,108].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [107]
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Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · cited 1× · see citing works
“Honeycomb microglial networks circumscribed individual surviving astrocytes in the glial limitans and were induced to do so by release of ATP from connexin hemichannels and detection by purinergic receptors (P2X4 and P2Y12) 16, 17, 19, 20 .”
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 · cited 1× · see citing works
“Honeycomb microglial networks circumscribed individual surviving astrocytes in the glial limitans and were induced to do so by release of ATP from connexin hemichannels and detection by purinergic receptors (P2X4 and P2Y12) 16, 17, 19, 20 .”
Sterile inflammation: sensing and reacting to damage
Chen, G. Y., & Nuñez, G. (2010) · Nature Reviews Immunology · doi:10.1038/nri2873 · Cited by 3,051 · cited 1× · see citing works
“In the absence of GSH, the brain responded to damage by eliciting an anatomically partitioned sterile immune reaction 18 .”
Jung, S., Aliberti, J., Graemmel, P., Sunshine, M. J., Kreutzberg, G. W., Sher, A., & Littman, D. R. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.11.4106-4114.2000 · Cited by 2,632 · see citing works
The P2Y12 receptor regulates microglial activation by extracellular nucleotides
Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W.-B., & Julius, D. (2006) · Nature Neuroscience · doi:10.1038/nn1805 · Cited by 1,542 · cited 1× · see citing works
“Honeycomb microglial networks circumscribed individual surviving astrocytes in the glial limitans and were induced to do so by release of ATP from connexin hemichannels and detection by purinergic receptors (P2X4 and P2Y12) 16, 17, 19, 20 .”
Animal models of traumatic brain injury
Xiong, Y., Mahmood, A., & Chopp, M. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3407 · Cited by 1,413 · cited 1× · see citing works
“moderate, and severe forms of injury 5 , but therapeutic research in these models has not yet translated successfully into the clinic 4, 13 .”
Changing patterns in the epidemiology of traumatic brain injury
Roozenbeek, B., Maas, A. I. R., & Menon, D. K. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.22 · Cited by 1,368 · see citing works
Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation
McDonald, B., Pittman, K., Menezes, G. B., Hirota, S. A., Slaba, I., Waterhouse, C. C. M., Beck, P. L., Muruve, D. A., & Kubes, P. (2010) · Science · doi:10.1126/science.1195491 · Cited by 1,210 · cited 1× · see citing works
“While microglia protected the parenchyma, myelomonocytic cells invaded the damaged meninges in a P2X7-and pannexin-dependent manner consistent with a recent study showing P2X7-dependent neutrophil recruitment into the injured liver 21 .”
Free Radical Pathways in CNS Injury
LEWÉN, A., MATZ, P., & CHAN, P. H. (2000) · Journal of Neurotrauma · doi:10.1089/neu.2000.17.871 · Cited by 759 · cited 1× · see citing works
“ROS is commonly observed in TBI lesions 7, 8 , and transcranial delivery of GSH preserved the glial limitans, reduced cell death, and eliminated the sterile injury response.”
Faust, N., Varas, F., Kelly, L. M., Heck, S., & Graf, T. (2000) · Blood · doi:10.1182/blood.v96.2.719 · Cited by 751 · see citing works
Purinergic Signaling during Inflammation
Eltzschig, H. K., Sitkovsky, M. V., & Robson, S. C. (2012) · New England Journal of Medicine · doi:10.1056/nejmra1205750 · Cited by 716 · cited 4× · see citing works
“The following antagonists from Sigma were used: TNP-ATP hydrase (P2X4; 25 mM), oxidated ATP (P2X7; 10 mM), MRS2578 (P2Y6; diluted a 50 mM DMSO stock 1:100 in aCSF to a final concentration of 500 µM), MeSAMP (P2Y12; 10 mM), carbenoxolone (CBX) (connexin hemichannels; 100 mM), Provenecid (pannexin hemichannels; 100 mM),…”
InfluentialPurinergic Signaling during Inflammation
Eltzschig, H. K., Mv, S., & Robson, S. C. (2013) · New England Journal of Medicine · doi:10.1056/nejmc1300259 · Cited by 608 · see citing works
Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood
Zetterberg, H., Smith, D. H., & Blennow, K. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.9 · Cited by 601 · cited 1× · see citing works
“B6 LysM-GFP heterozygous knock-in mice (LysM gfp/+ ) were generously provided by Dr. Thomas Graf (Albert Einstein College of Medicine) 3 and maintained at the NIH.”
Factors affecting excitatory amino acid release following severe human head injury
Bullock, R., Zauner, A., Woodward, J. J., Myseros, J., Choi, S. C., Ward, J. D., Marmarou, A., & Young, H. F. (1998) · Journal of Neurosurgery · doi:10.3171/jns.1998.89.4.0507 · Cited by 526 · see citing works
Thinned-skull cranial window technique for long-term imaging of the cortex in live mice
Yang, G., Pan, F., Parkhurst, C. N., Grutzendler, J., & Gan, W. (2010) · Nature Protocols · doi:10.1038/nprot.2009.222 · Cited by 438 · see citing works
Choice of cranial window type for in vivo imaging affects dendritic spine turnover in the cortex
Xu, H., Pan, F., Yang, G., & Gan, W. (2007) · Nature Neuroscience · doi:10.1038/nn1883 · Cited by 413 · cited 2× · see citing works
“Over a period of 30 months, 142 patients were enrolled with a baseline Glasgow Coma Scale (GCS) of 15, reporting loss-of-consciousness or post-traumatic amnesia, and a clinical computed tomography (CT) scan without evidence of injury to the parenchyma.”
Live Astrocytes Visualized by Green Fluorescent Protein in Transgenic Mice
Zhuo, L., Sun, B., Zhang, C.-L., Fine, A., Chiu, S. Y., & Messing, A. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8601 · Cited by 364 · see citing works
Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers
DeKosky, S. T., Blennow, K., Ikonomović, M. D., & Gandy, S. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.36 · Cited by 270 · see citing works
Brain Hydroxyl Radical Generation in Acute Experimental Head Injury
Hall, E. D., Andrus, P. K., & Yonkers, P. A. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03189.x · Cited by 229 · cited 1× · see citing works
“ROS is commonly observed in TBI lesions 7, 8 , and transcranial delivery of GSH preserved the glial limitans, reduced cell death, and eliminated the sterile injury response.”
Role of Calcium in Central Nervous System Injuries
Young, W. (1992) · Journal of Neurotrauma · doi:10.1177/089771519200901s02 · Cited by 163 · see citing works
Evidence for Prolonged Release of Excitatory Amino Acids in Severe Human Head Trauma
Bullock, R. M., Zauner, A., Myseros, J. S., Marmarou, A., Woodward, J. J., & Young, H. F. (1995) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1995.tb16586.x · Cited by 161 · see citing works
A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury
McConeghy, K. W., Hatton, J., Hughes, L., & Cook, A. M. (2012) · CNS Drugs · doi:10.2165/11634020-000000000-00000 · Cited by 158 · cited 2× · see citing works
“moderate, and severe forms of injury 5 , but therapeutic research in these models has not yet translated successfully into the clinic 4, 13 .”
Mazzeo, A. T., Alessandri, B., Singh, A., & Bullock, M. R. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.05.026 · Cited by 137 · see citing works
Neuroinflammation: beneficial and detrimental effects after traumatic brain injury
Finnie, J. (2013) · InflammoPharmacology · doi:10.1007/s10787-012-0164-2 · Cited by 136 · cited 1× · see citing works
“Collectively, our data suggest that the acute inflammatory reaction to brain injury is beneficial 6 .”
Mamourian, A. C., Hoopes, P. J., & Lewis, L. D. (2000) · PubMed · Cited by 95 · see citing works
Exploring new routes for neuroprotective drug development in traumatic brain injury
Janowitz, T., & Menon, D. K. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000330 · Cited by 74 · cited 1× · see citing works
“moderate, and severe forms of injury 5 , but therapeutic research in these models has not yet translated successfully into the clinic 4, 13 .”
Chuang, K., Koretsky, A. P., & Sotak, C. H. (2009) · Magnetic Resonance in Medicine · doi:10.1002/mrm.21962 · Cited by 63 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microglia and macrophages in brain homeostasis and disease
Li, Q., & Barres, B. A. (2018) · Nature Reviews Immunology · doi:10.1038/nri.2017.125 · Cited by 1,999 · see citing works
Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells
Benakis, C., Brea, D., Caballero, S., Faraco, G., Moore, J., Murphy, M., Sita, G., Racchumi, G., Ling, L., Pamer, E. G., et al. (2016) · Nature Medicine · doi:10.1038/nm.4068 · Cited by 1,114 · see citing works
Microglia development and function
Nayak, D., Roth, T. L., & McGavern, D. B. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120240 · Cited by 1,154 · see citing works
Inflammation and neuroprotection in traumatic brain injury.
Corps, K. N., Roth, T. L., & McGavern, D. B. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.3558 · Cited by 853 · see citing works
Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.010 · Cited by 799 · see citing works
Astrocyte roles in traumatic brain injury
Burda, J. E., Bernstein, A. M., & Sofroniew, M. V. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.03.020 · Cited by 758 · see citing works
Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma
Cugurra, A., Mamuladze, T., Rustenhoven, J., Dykstra, T., Beroshvili, G., Greenberg, Z. J., Baker, W., Papadopoulos, Z., Drieu, A., Blackburn, S., et al. (2021) · Science · doi:10.1126/science.abf7844 · Cited by 681 · see citing works
The contribution of astrocytes and microglia to traumatic brain injury
Karve, I. P., Taylor, J. M., & Crack, P. J. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13125 · Cited by 651 · see citing works
Regulated necrosis: disease relevance and therapeutic opportunities
Conrad, M., Angeli, J. P. F., Vandenabeele, P., & Stockwell, B. R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.6 · Cited by 630 · see citing works
Modulating the stem cell niche for tissue regeneration
Lane, S., Williams, D. A., & Watt, F. M. (2014) · Nature Biotechnology · doi:10.1038/nbt.2978 · Cited by 616 · see citing works
Innate immune responses to trauma
Huber-Lang, M. S., Lambris, J. D., & Ward, P. A. (2018) · Nature Immunology · doi:10.1038/s41590-018-0064-8 · Cited by 604 · see citing works
Madry, C., Kyrargyri, V., Arancibia-Cárcamo, I. L., Jolivet, R., Kohsaka, S., Bryan, R. M., & Attwell, D. (2018) · Neuron · doi:10.1016/j.neuron.2017.12.002 · Cited by 464 · see citing works
Microglial Activation in Traumatic Brain Injury
Donat, C. K., Scott, G., Gentleman, S., & Sastre, M. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00208 · Cited by 489 · see citing works
Defining ROS in Biology and Medicine
Li, Y. R., & Trush, M. A. (2016) · Reactive Oxygen Species · doi:10.20455/ros.2016.803 · Cited by 484 · see citing works
“Due to the fact that ROS and inflammation are intimately intertwined [10, 11], many antioxidant enzymes or proteins, as well as non-protein antioxidants also possess antiinflammatory activities [12].”
BackgroundInflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532 · see citing works
Microglia morphophysiological diversity and its implications for the CNS
Vidal-Itriago, A., Radford, R. A. W., Aramideh, J. A., Maurel, C., Scherer, N. M., Don, E. K., Lee, A., Chung, R. S., Graeber, M. B., & Morsch, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.997786 · Cited by 412 · see citing works
“Inhibition of microglia through P2RY6 antagonism likewise resulted in increased parenchymal cell death 12 hours after compression injury (126).”
BackgroundInfluentialA Materials Roadmap to Functional Neural Interface Design
Wellman, S. M., Eles, J. R., Ludwig, K. A., Seymour, J. P., Michelson, N. J., McFadden, W. E., Vazquez, A. L., & Kozai, T. D. Y. (2018) · Advanced Functional Materials · doi:10.1002/adfm.201701269 · Cited by 389 · see citing works
Brain capillary pericytes exert a substantial but slow influence on blood flow
Hartmann, D. A., Berthiaume, A., Grant, R. I., Harrill, S. A., Koski, T., Costello, J., Tieu, T., McDowell, K. P., Faino, A., Kelly, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00793-2 · Cited by 399 · see citing works
Erickson, M. A., & Banks, W. A. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014647 · Cited by 393 · see citing works
P2X7 receptor: an emerging target in central nervous system diseases
Sperlágh, B., & Illes, P. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.08.002 · Cited by 390 · see citing works
Traumatic Brain Injury Imaging in the Second Near‐Infrared Window with a Molecular Fluorophore
Zhang, X., Wang, H., Antaris, A. L., Li, L., Diao, S., Ma, R., Nguyen, A., Hong, G., Ma, Z., Wang, J., et al. (2016) · Advanced Materials · doi:10.1002/adma.201600706 · Cited by 386 · see citing works
Inflammatory neuroprotection following traumatic brain injury
Russo, M. V., & McGavern, D. B. (2016) · Science · doi:10.1126/science.aaf6260 · Cited by 380 · see citing works
Multifaceted interactions between adaptive immunity and the central nervous system
Kipnis, J. (2016) · Science · doi:10.1126/science.aag2638 · Cited by 376 · see citing works
Dealing with danger in the CNS: the response of the immune system to injury
Gadani, S. P., Walsh, J. T., Lukens, J. R., & Kipnis, J. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.019 · Cited by 342 · see citing works
Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis.
Bolte, A. C., Dutta, A. B., Hurt, M. E., Smirnov, I., Kovacs, M. A., McKee, C. A., Ennerfelt, H. E., Shapiro, D., Nguyen, B. H., Frost, E. L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18113-4 · Cited by 357 · see citing works
Purinergic receptor P2RY12-dependent microglial closure of the injured blood–brain barrier
Lou, N., Takano, T., Pei, Y., Xavier, A. L., Goldman, S. A., & Nedergaard, M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520398113 · Cited by 364 · see citing works
Qi, J., Chen, C., Zhang, X., Hu, X., Ji, S., Kwok, R. T. K., Lam, J. W. Y., Ding, D., & Tang, B. Z. (2018) · Nature Communications · doi:10.1038/s41467-018-04222-8 · Cited by 350 · see citing works
Alves de Lima, K., Rustenhoven, J., & Kipnis, J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-102319-103410 · Cited by 348 · see citing works
Shinozaki, Y., Shibata, K., Yoshida, K., Shigetomi, E., Gachet, C., Ikenaka, K., Tanaka, K. F., & Koizumi, S. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.047 · Cited by 341 · see citing works
Myeloid Cells in the Central Nervous System
Herz, J., Filiano, A. J., Wiltbank, A. T., Yogev, N., & Kipnis, J. (2017) · Immunity · doi:10.1016/j.immuni.2017.06.007 · Cited by 332 · see citing works
The anatomy and immunology of vasculature in the central nervous system
Mastorakos, P., & McGavern, D. (2019) · Science Immunology · doi:10.1126/sciimmunol.aav0492 · Cited by 333 · see citing works
Self-citationThe Dynamics of Apoptotic Cell Clearance
Elliott, M. R., & Ravichandran, K. S. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.06.029 · Cited by 314 · see citing works
Advances in Meningeal Immunity
Rua, R., & McGavern, D. B. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.04.003 · Cited by 326 · see citing works
“Sterile Injury Triggers Meningeal Inflammation Traumatic brain injury (TBI) affects more than 2 million people in the United States every year, and there are currently no highly effective treatments available [105].”
InfluentialCellular infiltration in traumatic brain injury
Alam, A., Thelin, E. P., Tajsic, T., Khan, D. Z., Khellaf, A., Patani, R., & Helmy, A. E. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02005-x · Cited by 298 · see citing works
Microglial TREM2/DAP12 signaling: a double-edged sword in neural diseases
Konishi, H., & Kiyama, H. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00206 · Cited by 300 · see citing works
“However, upon neuronal injury and in neurodegenerative diseases, microglia become activated, and transform into a hypertrophic or ameboid shape (Lobsiger et al., 2013; Roth et al., 2014; Fernández-Arjona et al., 2017).”
BackgroundSepsis-associated encephalopathy: A vicious cycle of immunosuppression
Ren, C., Yao, R.-Q., Zhang, H., Feng, Y.-W., & Yao, Y.-M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1701-3 · Cited by 259 · see citing works
Liu, H., Li, Y., Sun, S., Xin, Q., Liu, S., Mu, X., Yuan, X., Chen, K., Wang, H., Varga, K., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20275-0 · Cited by 275 · see citing works
Identification of direct connections between the dura and the brain
Smyth, L. C. D., Xu, D., Okar, S. V., Dykstra, T., Rustenhoven, J., Papadopoulos, Z., Bhasiin, K., Kim, M. W., Drieu, A., Mamuladze, T., et al. (2024) · Nature · doi:10.1038/s41586-023-06993-7 · Cited by 264 · see citing works
A novel neutrophil subset promotes CNS neuron survival and axon regeneration
Sas, A., Carbajal, K. S., Jerome, A., Menon, R., Yoon, C., Kalinski, A. L., Giger, R., & Segal, B. (2020) · Nature Immunology · doi:10.1038/s41590-020-00813-0 · Cited by 226 · see citing works
“Although a few published studies have suggested that neutrophils may play a beneficial role in the context of CNS trauma 31,32 , we are the first to characterize this singular CD14 + Ly6G low subset and its biological functions.”
Chou, A., Krukowski, K., Jopson, T. D., Zhu, P., Costa‐Mattioli, M., Walter, P., & Rosi, S. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1707661114 · Cited by 253 · see citing works
Brain borders at the central stage of neuroimmunology
Rustenhoven, J., & Kipnis, J. (2022) · Nature · doi:10.1038/s41586-022-05474-7 · Cited by 253 · see citing works
Neurosteroids as regulators of neuroinflammation
Yılmaz, C., Karali, K., Fodelianaki, G., Gravanis, A., Chavakis, T., Charalampopoulos, I., & Alexaki, V. I. (2019) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2019.100788 · Cited by 245 · see citing works
“Upon TBI microglia extend processes toward the site of damage (Davalos et al., 2005; Roth et al., 2014; Nimmerjahn et al., 2005).”
Baik, S. H., Kang, S., Son, S. M., & Mook-Jung, I. (2016) · Glia · doi:10.1002/glia.23074 · Cited by 234 · see citing works
Neutrophil swarming: an essential process of the neutrophil tissue response
Kienle, K., & Lämmermann, T. (2016) · Immunological Reviews · doi:10.1111/imr.12458 · Cited by 227 · see citing works
Morganti, J. M., Jopson, T. D., Liu, S., Riparip, L.-K., Guandique, C. K., Gupta, N., Ferguson, A. R., & Rosi, S. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2405-14.2015 · Cited by 253 · see citing works
“This finding was similar to recent observations in a skull compression model of brain injury (Roth et al., 2014).”
ResultLiu, H., Li, Y., Sun, S., Xin, Q., Liu, S., Mu, X., Yuan, X. F., Chen, K., Wang, H., Varga, K., et al. (2021) · RePEc: Research Papers in Economics · Cited by 229 · see citing works
Priming the Inflammatory Pump of the CNS after Traumatic Brain Injury
Witcher, K. G., Eiferman, D. S., & Godbout, J. P. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.08.002 · Cited by 222 · see citing works
Post-traumatic headache: epidemiology and pathophysiological insights
Ashina, H., Porreca, F., Anderson, T. R., Amin, F. M., Ashina, M., Schytz, H. W., & Dodick, D. W. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0243-8 · Cited by 221 · see citing works
Greenhalgh, 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 211 · 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.”
BackgroundMethodInfluentialLncRNA GAS5 inhibits microglial M2 polarization and exacerbates demyelination
Sun, D., Yu, Z., Xue, F., Liu, M., Pu, Y., Shao, Q., Wang, D., Zhao, X., Huang, A., Xiang, Z., et al. (2017) · EMBO Reports · doi:10.15252/embr.201643668 · Cited by 209 · see citing works
Six Degree-of-Freedom Measurements of Human Mild Traumatic Brain Injury
Hernandez, F., Wu, L. C., Yip, M. C., Laksari, K., Hoffman, A. R., López, J. R., Grant, G. A., Kleiven, S., & Camarillo, D. B. (2014) · Annals of Biomedical Engineering · doi:10.1007/s10439-014-1212-4 · Cited by 194 · see citing works
Immune Surveillance of the CNS following Infection and Injury
Russo, M. V., & McGavern, D. B. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.002 · Cited by 191 · see citing works
Self-citationNeutrophils in traumatic brain injury (TBI): friend or foe?
Liu, Y., Li, S., & Dai, S.-S. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1173-x · Cited by 191 · see citing works
Schafflick, D., Wolbert, J., Heming, M., Thomas, C., Hartlehnert, M., Börsch, A., Ricci, A., Martín-Salamanca, S., Li, X., Lu, I., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00880-y · Cited by 181 · see citing works
Dissemination 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
A Binary Cre Transgenic Approach Dissects Microglia and CNS Border-Associated Macrophages
Kim, J.-S., Kolesnikov, M., Peled-Hajaj, S., Scheyltjens, I., Xia, Y., Trzebanski, S., Haimon, Z., Shemer, A., Lubart, A., Van Hove, H., et al. (2021) · Immunity · doi:10.1016/j.immuni.2020.11.007 · Cited by 176 · see citing works
DAMP sensing and sterile inflammation: intracellular, intercellular and inter-organ pathways
Huang, Y., Jiang, W., & Zhou, R. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01027-3 · Cited by 189 · see citing works
“Transcranial administration of the reactive oxygen species scavenger, glutathione, ameliorates these purine receptor-dependent inflammatory responses and therapeutically improves brain injury 120 .”
The multiple faces of leukocyte interstitial migration
Lämmermann, T., & Germain, R. N. (2014) · Seminars in Immunopathology · doi:10.1007/s00281-014-0418-8 · Cited by 169 · see citing works
High-resolution in vivo imaging of mouse brain through the intact skull
Park, J., Sun, W., & Cui, M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505939112 · Cited by 162 · see citing works
Jimenez‐Pacheco, A., Dı́az-Hernández, M., Arribas-Blázquez, M., Sanz‐Rodriguez, A., Olivos-Oré, L. A., Artalejo, A. R., Alves, M., Letavic, M. A., Miras‐Portugal, M. T., Conroy, R. M., et al. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4009-15.2016 · Cited by 161 · see citing works
Emergence of large-scale cell death through ferroptotic trigger waves
Co, H. K. C., Wu, C., Lee, Y., & Chen, S. (2024) · Nature · doi:10.1038/s41586-024-07623-6 · Cited by 160 · see citing works
“…or treatment with ferroptosis inducers (such as erastin (an inhibitor of the cystine–glutamate anti-porter xCT) and RSL3 (an inhibitor of glutathione peroxidase 4; GPX4)), spreads across human retinal pigment epithelial (RPE) cells as a series of spatially coupled death events (Extended Data Fig.”
Magtanong, L., & Dixon, S. J. (2018) · Developmental Neuroscience · doi:10.1159/000496922 · Cited by 155 · see citing works
Traumatic Brain Injury: Imaging Patterns and Complications
Schweitzer, A. D., Niogi, S. N., Whitlow, C. J., & Tsiouris, A. J. (2019) · Radiographics · doi:10.1148/rg.2019190076 · Cited by 153 · see citing works
Unraveling the Truth About Antioxidants: ROS and disease: finding the right balance
Kawagishi, H., & Finkel, T. (2014) · Nature Medicine · doi:10.1038/nm.3625 · Cited by 152 · see citing works
Neuroinflammation as a Factor of Neurodegenerative Disease: Thalidomide Analogs as Treatments
Jung, Y. J., Tweedie, D., Scerba, M. T., & Greig, N. H. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00313 · Cited by 154 · see citing works
Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury
Logsdon, A. F., Lucke-Wold, B. P., Turner, R. C., Huber, J. D., Rosen, C. L., & Simpkins, J. W. (2015) · Comprehensive physiology · doi:10.1002/cphy.c140057 · Cited by 172 · see citing works
Russo, M. V., Latour, L. L., & McGavern, D. B. (2018) · Nature Immunology · doi:10.1038/s41590-018-0086-2 · Cited by 149 · 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
“Perivascular spaces and meninges seem particularly vulnerable to alignment of neutrophils after cortical injury [37, 111].”
Xu, D., Fan, L., Gao, L., Xiong, Y., Wang, Y., Ye, Q., Yu, A., Dai, H., Yin, Y., Cai, J., et al. (2016) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.6b03555 · Cited by 147 · see citing works
Macrophage and microglial plasticity in the injured spinal cord
David, S., Greenhalgh, A. D., & Kroner, A. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.08.064 · Cited by 141 · see citing works
Optic nerve astrocyte reactivity protects function in experimental glaucoma and other nerve injuries
Sun, D., Moore, S., & Jakobs, T. C. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20160412 · Cited by 130 · see citing works
Webster, K. M., Wright, D. K., Sun, M., Semple, B. D., Öztürk, E., Stein, D. G., O'Brien, T. J., & Shultz, S. R. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0457-7 · Cited by 137 · see citing works
Gao, H., Danzi, M. C., Choi, C. S., Taherian, M., Hansen, C. D., Ellman, D. G., Madsen, P. M., Bixby, J. L., Lemmon, V., Lambertsen, K. L., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.11.083 · Cited by 136 · see citing works
Wang, Z., Cheng, Y. H., Yu, X., Ye, L.-B., Xia, Q.-H., Johnson, N. R., Wei, X., Chen, D., Cao, G., Fu, X., et al. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9583-6 · Cited by 138 · see citing works
Microglia and the Purinergic Signaling System
Calovi, S., Mut-Arbona, P., & Sperlágh, B. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.12.021 · Cited by 133 · see citing works
Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease
Derk, J., Jones, H. E., Como, C., Pawlikowski, B., & Siegenthaler, J. A. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.703944 · Cited by 120 · see citing works
Heat-Shock Proteins in Neuroinflammation
Dukay, B., Csoboz, B., & Tóth, M. E. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00920 · Cited by 132 · see citing works
Xiao, M., Liu, C. X., Zhou, L. G., Yang, Y., & Wang, Y. (2023) · Medicine · doi:10.1097/md.0000000000032991 · Cited by 138 · see citing works
Lipids in the intensive care unit: Recommendations from the ESPEN Expert Group
Calder, P. C., Adolph, M., Deutz, N. E., Grau, T., Innes, J. K., Klek, S., Lev, S., Mayer, K., Michael-Titus, A. T., Pradelli, L., et al. (2018) · Clinical Nutrition · doi:10.1016/j.clnu.2017.08.032 · Cited by 158 · see citing works
“It has also been demonstrated that after mild compression injury in mice, heterogeneity of microglia at the site develops alongside a coordinated microglial response [186].”
BackgroundTargeting 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
“Morphological changes in microglia begin within minutes and can clearly be seen by at least 6 h after the injury (Bachstetter et al. 2013; Roth et al. 2014).”
Clark, D. P. Q., Perreau, V. M., Shultz, S. R., Brady, R. D., Lei, E., Dixit, S., Taylor, J. M., Beart, P. M., & Boon, W. C. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02721-8 · Cited by 127 · see citing works
Coles, J. A., Myburgh, E., Brewer, J. M., & McMenamin, P. G. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.05.002 · Cited by 123 · see citing works
Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity
Rua, R., Lee, J. Y., Silva, A. B., Swafford, I. S., Maric, D., Johnson, K. R., & McGavern, D. B. (2019) · Nature Immunology · doi:10.1038/s41590-019-0344-y · Cited by 123 · see citing works
“We demonstrated previously that the skull bone is permeable to small molecules 18 , and our hydrogel approach allowed acetylcholine to be delivered transcranially into the meninges.”
Monocyte-derived IL-6 programs microglia to rebuild damaged brain vasculature
Choi, B., Johnson, K. R., Maric, D., & McGavern, D. B. (2023) · Nature Immunology · doi:10.1038/s41590-023-01521-1 · Cited by 121 · see citing works
Eles, J. R., Vazquez, A. L., Snyder, N. R., Lagenaur, C. F., Murphy, M. C., Kozai, T. D. Y., & Cui, X. T. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.10.054 · Cited by 116 · see citing works
The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap
Walker, K. A., Page, L. M. L., Terrando, N., Duggan, M. R., Heneka, M. T., & Bettcher, B. M. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00627-2 · Cited by 118 · see citing works
Microglia-Astrocyte Communication in Alzheimer’s Disease
Wu, Y., & Eisel, U. L. M. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230199 · Cited by 118 · see citing works
“Microglia undergo a remarkable transformation from their stationary to an active state in response to certain cues, such as brain injury [35] or immunological stimuli, and adopt a less ramified morphology and a more amoeboid morphology as their soma grows and their cellular processes shorten [36].”
Temporally distinct myeloid cell responses mediate damage and repair after cerebrovascular injury
Mastorakos, P., Mihelson, N., Luby, M., Burks, S. R., Johnson, K., Hsia, A. W., Witko, J., Frank, J. A., Latour, L., & McGavern, D. B. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00773-6 · Cited by 113 · see citing works
Self-citationDiffusion MRI and the detection of alterations following traumatic brain injury
Hutchinson, E. B., Schwerin, S. C., Avram, A., Juliano, S. L., & Pierpaoli, C. M. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24065 · Cited by 108 · see citing works
Macrophages on the margin: choroid plexus immune responses
Cui, J., Xu, H., & Lehtinen, M. K. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.07.002 · Cited by 110 · see citing works
Wang, W., Li, K., Ma, W., Li, Y., Liu, F., Kong, Y., Wang, L., Yi, F., Sang, Y., Li, G., et al. (2025) · Nature Materials · doi:10.1038/s41563-025-02214-w · Cited by 110 · see citing works
Translational potential of astrocytes in brain disorders
Verkhratsky, A., Steardo, L., Parpura, V., & Montana, V. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.09.003 · Cited by 110 · see citing works
Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury
Norris, G. T., Smirnov, I., Filiano, A. J., Shadowen, H. M., Cody, K. R., Thompson, J. A., Harris, T. H., Gaultier, A., Overall, C. C., & Kipnis, J. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20172244 · Cited by 109 · see citing works
“The professional phagocytes in the central nervous system (CNS) are microglia, which are capable of responding rapidly to tissue damage by extending cell processes, engulfing debris, and undergoing proliferation (Davalos et al., 2005; Nimmerjahn et al., 2005; Aguzzi et al., 2013; Roth et al., 2014; Ulland et al., 2015…”
BackgroundLämmermann, T. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.1mr0915-403 · Cited by 108 · see citing works
Supplements, nutrition, and alternative therapies for the treatment of traumatic brain injury
Lucke-Wold, B. P., Logsdon, A. F., Nguyen, L., Eltanahay, A., Turner, R. C., Bonasso, P. C., Knotts, C. M., Moeck, A., Maroon, J. C., Bailes, J. E., et al. (2016) · Nutritional Neuroscience · doi:10.1080/1028415x.2016.1236174 · Cited by 108 · see citing works
Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage
Rustenhoven, J., Pavlou, G., Storck, S. E., Dykstra, T., Du, S., Wan, Z., Quintero, D., Scallan, J. P., Smirnov, I., Kamm, R. D., et al. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20221929 · Cited by 107 · see citing works
“Additionally, transcranial delivery of small molecules through the cranium has proved effective in limiting neuroinflammatory responses in the CNS borders and reaches the dural mater (Roth et al., 2014).”
BackgroundLuo, W., Yang, Z., Zheng, J., Cai, Z., Li, X., Liu, J., Guo, X., Luo, M., Fan, X., Cheng, M., et al. (2024) · ACS Nano · doi:10.1021/acsnano.4c09097 · Cited by 106 · see citing works
Efficacy of N-Acetyl Cysteine in Traumatic Brain Injury
Eakin, K. C., Baratz-Goldstein, R., Pick, C. G., Zindel, O., Balaban, C. D., Hoffer, M. E., Lockwood, M. M., Miller, J. P., & Hoffer, B. J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090617 · Cited by 105 · see citing works
White matter damage after traumatic brain injury: A role for damage associated molecular patterns
Braun, M., Vaibhav, K., Saad, N., Fatima, S., Vender, J. R., Baban, B., Hoda, M. N., & Dhandapani, K. M. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.05.020 · Cited by 104 · see citing works
Chen, X., Pan, Z., Fang, Z., Lin, W., Wu, S., Yang, F., Li, Y., Fu, H., Gao, H., & Li, S. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1345-8 · Cited by 104 · see citing works
Retracted
- Authors
- Roth, T. L., Nayak, D., Atanasijevic, T., Koretsky, A. P., Latour, L. L., & McGavern, D. B.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- McGavern, Dorian B.
- Venue
- Nature
- Published
- 2013-12-08
- Volume
- 505
- Issue
- 7482
- Pages
- 223-228
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3930079
- OpenAlex
- W2055797258
- Cited by
- 574
- References
- 27
- Citations by year
- 2026: 30 · 2025: 46 · 2024: 45 · 2023: 42 · 2022: 62 · 2021: 50 · 2020: 49 · 2019: 51 · 2018: 48 · 2017: 39 · 2016: 50 · 2015: 38 · 2014: 24
- FWCI
- 23.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (ZIANS003112)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Automotive and Human Injury Biomechanics
- Keywords
- traumatic brain injury, meningeal inflammation, purinergic receptor antagonists, glutathione, reactive oxygen species, microglia, neutrophils, vascular injury, neuroinflammation, intravital microscopy
- MeSH terms
- Administration, Topical, Animals, Antioxidants, Astrocytes, Brain, Brain Injuries, Disease Models, Animal, Encephalitis, Glutathione, Humans, Male, Meninges, Neutrophils, Skull, Glasgow Coma Scale, Cell Death, Rats, Sprague-Dawley, Reactive Oxygen Species, Microglia, Receptors, Purinergic P2, Neuroprotective Agents, Intracranial Hemorrhages, Mice, Rats, Receptors, Purinergic P2X7, Purinergic P2 Receptor Antagonists
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