Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation
Open accessAbstract
Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood–brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b + antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.
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Insoluble fibrinogen or fibrin can be deposited in brain and drive adaptive immune responses and microglial inflammation.
“For example, insoluble fibrinogen or fibrin can be deposited in brain and drive adaptive immune responses as well as microglial inflammation (Ryu et al., 2015).”
From A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer’s Disease (2017) · cites this paper as Ryu et al., 2015
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“to CD11b/CD18 receptor (integrin aMb2) activation in antigen presenting cells, since pharmacological blockade or genetic deletion of CD11b inhibits fibrinogen-driven demyelination.(83) Depletion of fibrinogen using ancrod reduces inflammation and axonal dam-”
BackgroundInfluentialKeep, R. F., Andjelkovic, A. V., Xiang, J., Stamatovic, S. M., Antonetti, D. A., Hua, Y., & Xi, G. (2018) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x18774666 · Cited by 183 · see citing works
Pericytes regulate vascular immune homeostasis in the CNS
Török, O., Schreiner, B., Schaffenrath, J., Tsai, H.-C., Maheshwari, U., Stifter, S. A., Welsh, C., Amorim, A., Sridhar, S., Utz, S. G., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016587118 · Cited by 166 · see citing works
“Proceedings of the National Academy of Sciences of the United States of America, 118(10):e2016587118.”
BackgroundMechanical disruption of the blood–brain barrier following experimental concussion
Johnson, V. E., Weber, M. T., Xiao, R., Cullen, D. K., Meaney, D. F., Stewart, W. B., Jr., & Smith, D. H. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1824-0 · Cited by 156 · see citing works
Advanced MRI and staging of multiple sclerosis lesions
Absinta, M., Sati, P., & Reich, D. S. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.59 · Cited by 156 · see citing works
Mononuclear phagocytes locally specify and adapt their phenotype in a multiple sclerosis model
Locatelli, G., Theodorou, D., Kendirli, A., Jordão, M. J. C., Staszewski, O., Phulphagar, K., Cantuti-Castelvetri, L., Dagkalis, A., Bessis, A., Simons, M., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0212-3 · Cited by 155 · see citing works
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Welton, J. L., Loveless, S., Stone, T., von Ruhland, C., Robertson, N. P., & Clayton, A. (2017) · Journal of Extracellular Vesicles · doi:10.1080/20013078.2017.1369805 · Cited by 142 · see citing works
“[30] to promote autoimmunity and induce inflammatory demyelination.”
BackgroundA high-fat diet promotes depression-like behavior in mice by suppressing hypothalamic PKA signaling
Vagena, E., Ryu, J. K., Baeza-Raja, B., Walsh, N. M., Syme, C. A., Day, J. P., Houslay, M. D., & Baillie, G. S. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0470-1 · Cited by 134 · see citing works
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Fibrin drives thromboinflammation and neuropathology in COVID-19
Ryu, J. K., Yan, Z., Montano, M., Sozmen, E. G., Dixit, K., Suryawanshi, R. K., Matsui, Y., Helmy, E., Kaushal, P., Makanani, S. K., et al. (2024) · Nature · doi:10.1038/s41586-024-07873-4 · Cited by 116 · see citing works
“In a mouse model of fibrinogen-induced encephalomyelitis 35 , co-injection of spike PVs increased fibrin-induced microglial reactivity (Extended Data Fig.”
Self-citationDefining blood-induced microglia functions in neurodegeneration through multiomic profiling
Mendiola, A. S., Yan, Z., Dixit, K., Johnson, J. R., Bouhaddou, M., Meyer-Franke, A., Shin, M.-G., Yong, Y., Agrawal, A., MacDonald, E., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01522-0 · Cited by 124 · see citing works
Self-citationCSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients
Skillbäck, T. B., Delsing, L., Synnergren, J., Mattsson, N., Janelidze, S., Nägga, K., Kilander, L., Hicks, R., Wimo, A. B., Winblad, B. G., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.06.028 · Cited by 123 · see citing works
“…tightly controlled metabolic balance between vascular and brain cells and suboptimal control of exposure of the brain tissue to blood-associated substances, which ultimately may result in demyelination, axonal loss and cognitive impairment (Fornari et al., 2012, Iadecola, 2013, Ryu et al., 2015).”
Göbel, K., Pankratz, S., Asaridou, C.-M., Herrmann, A. M., Bittner, S., Merker, M., Ruck, T., Glumm, S., Langhauser, F., Kraft, P., et al. (2016) · Nature Communications · doi:10.1038/ncomms11626 · Cited by 123 · see citing works
Translating the biology of aging into novel therapeutics for Alzheimer disease
Hara, Y., McKeehan, N., & Fillit, H. M. (2018) · Neurology · doi:10.1212/wnl.0000000000006745 · Cited by 122 · see citing works
Lutz, S. E., Smith, J. R., Kim, D. H., Olson, C. V. L., Ellefsen, K. L., Bates, J. M., Gandhi, S., & Agalliu, D. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.094 · Cited by 114 · see citing works
“Endothelial tight junctions also prevent serum proteins such as fibrinogen from crossing the BBB, thereby conferring disease protection (Ryu et al., 2015).”
Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System
Luca, C. D., Colangelo, A. M., Alberghina, L., & Papa, M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00459 · Cited by 118 · see citing works
An Integrated View on Vascular Dysfunction in Alzheimer’s Disease
Klohs, J. (2019) · Neurodegenerative Diseases · doi:10.1159/000505625 · Cited by 111 · see citing works
Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex
Yates, R. L., Esiri, M. M., Palace, J. A., Jacobs, B. M., Perera, R., & DeLuca, G. C. (2017) · Annals of Neurology · doi:10.1002/ana.24997 · Cited by 111 · see citing works
“In experimental autoimmune encephalomyelitis (EAE), fibrinogen extravasation induces activation of microglia and subsequent axonal damage before onset of clinical signs, as well as promoting recruitment of myelin specific T cells.(8,9) Blocking the interaction of fibrinogen with microglia supresses relapsing paralysis…”
BackgroundLehallier, B., Shokhirev, M. N., Wyss‐Coray, T., & Johnson, A. A. (2020) · Aging Cell · doi:10.1111/acel.13256 · Cited by 106 · see citing works
“…• Treating mice with fibrinogen causes demyelination via the induction of adaptive immune responses and the recruitment of peripheral macrophages (Ryu et al., 2015) • Inhibiting fibrin with the monoclonal antibody 5B8 attenuates neurodegeneration and innate immunity in mouse models of…”
BackgroundMongan, D., Föcking, M., Healy, C., Susai, S. R., Heurich, M., Wynne, K. J., Nelson, B., McGorry, P. D., Amminger, G. P., Nordentoft, M., et al. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.2459 · Cited by 102 · see citing works
The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke
Ye, F., Garton, H. J. L., Hua, Y., Keep, R. F., & Xi, G. (2020) · Translational Stroke Research · doi:10.1007/s12975-020-00855-4 · Cited by 103 · see citing works
Endothelial Dysfunction in Neurodegenerative Diseases
Fang, Y., Hsieh, Y., Hu, C., & Tu, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032909 · Cited by 101 · see citing works
“Fibrinogen phosphorylates SMAD and causes oligodendrocyte progenitor cell (OPC) repression, leading to oligodendrocyte loss, followed by neurodegeneration [102].”
BackgroundNeuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases
Luca, C. D., Virtuoso, A., Maggio, N., & Papa, M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102128 · Cited by 93 · see citing works
“It activates the resident antigen-presenting cells, thus impairing the BBB and allowing for the margination and activation of specific T cells [122].”
BackgroundBlood will out: vascular contributions to Alzheimer’s disease
Strickland, S. (2018) · Journal of Clinical Investigation · doi:10.1172/jci97509 · Cited by 92 · see citing works
“In AD mice, anticoagulant treatment is protective (83–85) and injection of fibrinogen into the brain induces demyelination (86), reminiscent of the white matter abnormalities observed in AD patients discussed above.”
Fibrinogen scaffolds with immunomodulatory properties promote in vivo bone regeneration
Vasconcelos, D. M., Gonçalves, R. M., Almeida, C. R., Pereira, I. O., Oliveira, M. I., Nevès, N., da Silva, A. M., Ribeiro, A. C., Cunha, C., Almeida, A. R., et al. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.10.004 · Cited by 92 · see citing works
IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation
Psachoulia, K., Chamberlain, K. A., Heo, D., Davis, S. E., Paskus, J. D., Nanescu, S. E., Dupree, J. L., Wynn, T. A., & Huang, J. K. (2016) · Brain · doi:10.1093/brain/aww254 · Cited by 87 · see citing works
“Prominent infiltration of T cells into the CNS occurs following CNS injury or demyelination (Popovich et al., 1997; Ghasemlou et al., 2007; Ryu et al., 2015).”
BackgroundDoron, H., Amer, M., Ershaid, N., Blazquez, R., Shani, O., Lahav, T. G., Cohen, N., Adler, O., Hakim, Z., Pozzi, S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.033 · Cited by 87 · see citing works
“However, while CXCL10 was previously implicated in the recruitment of effector T cells to the brain in inflammatory diseases (Ryu et al., 2015) and in primary CNS tumors (De Waele et al., 2017), its function in recruiting T cells to brain metastases is unknown.”
BackgroundImaging meningeal inflammation in CNS autoimmunity identifies a therapeutic role for BTK inhibition
Bhargava, P., Kim, S., Reyes, A. A., Grenningloh, R., Boschert, U., Absinta, M., Pardo, C. A., van Zijl, P. C. M., Zhang, J., & Calabresi, P. A. (2021) · Brain · doi:10.1093/brain/awab045 · Cited by 80 · see citing works
Nanoplastic-induced vascular endothelial injury and coagulation dysfunction in mice
Wang, X., Jia, Z., Zhou, X., Su, L., Wang, M., Wang, T., & Zhang, H. (2022) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2022.161271 · Cited by 80 · see citing works
Emerging Role of Immunity in Cerebral Small Vessel Disease
Fu, Y., & Yan, Y. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00067 · Cited by 79 · see citing works
“found that fibrin in the neurovascular unit of MS models was sufficient to induce the activation of myelin-specific T cells and infiltration into the CNS, demonstrating that a fibrin-induced innate immune response triggers CNS autoimmunity (23, 40).”
BackgroundJeon, M.-T., Kim, K.-S., Kim, E. S., Lee, S., Kim, J., Hoe, H.-S., & Kim, D.-G. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101333 · Cited by 76 · see citing works
“mediator of the induction of autoimmune diseases (Ryu et al., 2015).”
BackgroundLoneliness: An Immunometabolic Syndrome
Pourriyahi, H., Yazdanpanah, N., Saghazadeh, A., & Rezaei, N. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph182212162 · Cited by 82 · see citing works
“It was found to increase autoimmune reactions, through the presentation of antigens and the release of chemokines [87].”
BackgroundIntraventricular Hemorrhage: the Role of Blood Components in Secondary Injury and Hydrocephalus
Garton, T. P., Keep, R. F., Wilkinson, D. A., Strahle, J. M., Hua, Y., Garton, H. J. L., & Xi, G. (2016) · Translational Stroke Research · doi:10.1007/s12975-016-0480-8 · Cited by 74 · see citing works
“However, recent evidence indicates that extravascular fibrinogen is a powerful pro-inflammatory mediator [44, 45] and may also play a role in mediating brain injury in”
BackgroundNeurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors
Lecordier, S., Manrique‐Castano, D., Moghrabi, Y. E., & ElAli, A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.727590 · Cited by 76 · see citing works
“BBB breakdown allows the infiltration into the parenchyma of toxic blood-born metabolites that accumulate around the vasculature, thus inducing macrophage, microglia, and T-cells activation and recruitment, which jointly promote axonal degeneration (Davalos et al., 2012; Ryu et al., 2015).”
BackgroundMagliozzi, R., Hametner, S., Facchiano, F., Marastoni, D., Rossi, S., Castellaro, M., Poli, A., Lattanzi, F., Visconti, A., Nicholas, R. S., et al. (2019) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.50893 · Cited by 73 · see citing works
“Fibrinogen was recently detected at the edge of chronic active but not inactive lesions of MS cases(35) and was demonstrated to stimulate a unique transcriptional signature in CD11b+/ CD18+ microglia that activate a cascade of pro-inflammatory events, including the recruitment and central nervous system (CNS) activati…”
BackgroundSelf-citationBreaking boundaries—coagulation and fibrinolysis at the neurovascular interface
Bardehle, S., Rafalski, V. A., & Akassoglou, K. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00354 · Cited by 76 · see citing works
“The serine protease tPA is an immediate-early response gene expressed in the brain (Bignami et al., 1982; Qian et al., 1993; Sappino et al., 1993; Carroll et al., 1994; Tsirka et al., 1995).”
BackgroundSelf-citationAndjelkovic, A. V., Xiang, J., Stamatovic, S. M., Hua, Y., Xi, G., Wang, M. M., & Keep, R. F. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.312816 · Cited by 68 · see citing works
Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination
Lee, N. J., Ha, S.-K., Sati, P., Absinta, M., Luciano, N. J., Lefeuvre, J., Schindler, M. K., Leibovitch, E. C., Ryu, J. K., Petersen, M. A., et al. (2018) · Brain · doi:10.1093/brain/awy082 · Cited by 65 · see citing works
“As fibrinogen has been investigated to be necessary and sufficient for early pathogenesis of inflammatory demyelination in rodents (Davalos et al., 2012; Ryu et al., 2015) but not in non-human primates, we investigated the spatiotemporal dynamics of fibrinogen deposition in marmoset EAE by creating a radiology-to-path…”
BackgroundInfluentialSelf-citationHou, Z., Wu, Y., Xu, C., Reghu, S., Shang, Z., Chen, J., Pranantyo, D., Marimuth, K., De, P. P., Ng, O. T., et al. (2020) · ACS Central Science · doi:10.1021/acscentsci.0c00755 · Cited by 60 · see citing works
Extracellular vesicles: translational challenges and opportunities
Clemmens, H., & Lambert, D. W. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180112 · Cited by 70 · see citing works
Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration
Winkler, A., Wrzos, C., Haberl, M., Weil, M., Gao, M., Möbius, W., Odoardi, F., Thal, D. R., Chang, M., Opdenakker, G., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci141694 · Cited by 60 · see citing works
“In EAE, fibrin(ogen) has been demonstrated to activate microglia, resulting in the release of chemokines, antigen presentation, and the recruitment of T cells and macrophages, aggravating demyelination (47, 48).”
BackgroundMetformin as a Potential Agent in the Treatment of Multiple Sclerosis
Dziedzic, A., Saluk, J., Miller, E. D., & Bijak, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21175957 · Cited by 59 · see citing works
Coagulation Pathways in Neurological Diseases: Multiple Sclerosis
Ziliotto, N., Bernardi, F., Jakimovski, D., & Zivadinov, R. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00409 · Cited by 59 · 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
“Fibrinogen induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination in models of multiple sclerosis (120).”
BackgroundHow does neurovascular unit dysfunction contribute to multiple sclerosis?
Cashion, J. M., Young, K. M., & Sutherland, B. A. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106028 · Cited by 57 · see citing works
Mendiola, A. S., Garza, R., Cardona, S. M., Mythen, S. A., Lira, S. A., Akassoglou, K., & Cardona, A. E. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00303 · Cited by 57 · see citing works
“The inflammatory effects of fibrinogen are associated with neurological diseases such as MS (Adams et al., 2007; Davalos et al., 2012; Ryu et al., 2015), stroke (Cheung et al., 2008) and AD (Flemming, 2014).”
BackgroundSelf-citationWillis, C. M., Nicaise, A. M., Ménoret, A., Ryu, J. K., Mendiola, A. S., Jellison, E. R., Givogri, M. I., Han, D. K. M., Bongarzone, E. R., Akassoglou, K., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816911116 · Cited by 55 · see citing works
“Shi M, et al. (2014) Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease.”
BackgroundResultInfluentialSelf-citationInflammation: major denominator of obesity, Type 2 diabetes and Alzheimer’s disease-like pathology?
Kacířová, M., Zmeškalová, A., Kořínková, L., Železná, B., Kuneš, J., & Maletı́nská, L. (2020) · Clinical Science · doi:10.1042/cs20191313 · Cited by 53 · see citing works
Montague-Cardoso, K., & Malcangio, M. (2021) · PAIN Reports · doi:10.1097/pr9.0000000000000879 · Cited by 53 · see citing works
“For instance, the BSCB is more permeable than the BBB to cytokines, such as TNFa,38 as well as small tracers such as [3H]-D-Mannitol.45 The fundamental building blocks of the BSCB are nonfenestrated capillary endothelial cells, a basal lamina, and pericyte and astrocyte foot processes.47 The endothelial cells are conn…”
Seyedsadr, M., Weinmann, O., Amorim, A., Ineichen, B., Egger, M., Mirnajafi-zadeh, J., Becher, B., Javan, M., & Schwab, M. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.11.018 · Cited by 47 · see citing works
Li, H., Ghorbani, S., Ling, C., Yong, V. W., & Xue, M. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106282 · Cited by 50 · see citing works
Yao, F., Luo, Y., Liu, Y.-C., Chen, Y., Li, Y.-T., Hu, X., You, X., Yu, S., Li, Z., Chen, L., et al. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00223-9 · Cited by 48 · see citing works
“The BSCB is impaired after SCI, and fibrinogen, as the main coagulation protein in plasma and inflammation inducer, leaks into the spinal cord parenchyma to cause an inflammatory response and microvascular remodeling [28, 29].”
BackgroundYue, Q., Leng, X., Xie, N., Zhang, Z., Yang, D., & Hoi, M. P. M. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70079 · Cited by 48 · see citing works
A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo
Motley, M. P., Madsen, D. H., Jürgensen, H. J., Spencer, D. E., Szabo, R., Holmbeck, K., Flick, M. J., Lawrence, D. A., Castellino, F., Weigert, R., et al. (2015) · Blood · doi:10.1182/blood-2015-05-644260 · Cited by 47 · see citing works
Li, H.-L., Huang, Y., Zhou, Y., Teng, R.-H., Zhou, S., Lin, J.-P., Yang, Y., Zhu, S., Xu, H. X., & Yao, Y.-X. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00477 · Cited by 47 · see citing works
“Past studies have reported that CXCL10 promotes the entry of peripheral immune cells into the spinal cord (24, 25).”
BackgroundToy, R., Pradhan, P., Ramesh, V., Paolo, N. C. D., Lash, B., Liu, J., Blanchard, E. L., Pinelli, C. J., Santangelo, P. J., Shayakhmetov, D. M., et al. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119512 · Cited by 46 · see citing works
Li, Y., Xie, L., Huang, T., Zhang, Y., Zhou, J., Qi, B., Wang, X., Chen, Z., & Li, P. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00778 · Cited by 46 · see citing works
Duan, J., Liang, S., Yu, Y., Li, Y., Wang, L., Wu, Z., Chen, Y., Miller, M. R., & Sun, Z. (2018) · Nanotoxicology · doi:10.1080/17435390.2018.1461267 · Cited by 45 · see citing works
“Fibrinogen as the precursor to fibrins is one of the most abundant coagulation factors, which can be rapidly transformed into fibrin monomer and insoluble fibrin polymer, making a prominent contribution to coagulation cascade and thrombus formation (Ryu et al. 2015).”
BackgroundInflammation and blood-brain barrier breach remote from the primary injury following neurotrauma
Smith, N. M., Giacci, M. K., Gough, A., Bailey, C. S. L., McGonigle, T. A., Black, A. M. B., Clarke, T. O., Bartlett, C. A., Iyer, K. S., Dunlop, S. A., et al. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1227-0 · Cited by 45 · see citing works
CCL 2 and CXCL 10 are associated with poor outcome after intracerebral hemorrhage
Landreneau, M. J., Mullen, M. T., Messe, S. R., Cucchiara, B. L., Sheth, K. N., McCullough, L. D., Kasner, S. E., Sansing, L. H., & the Serum Markers After Spontaneous Cerebral Hemorrhage (SMASCH) Investigators (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.595 · Cited by 44 · see citing works
Alruwaili, M., Al-Kuraishy, H. M., Alexiou, A. T., Papadakis, M., Alrashdi, B. M., Elhussieny, O., Saad, . M., & Batiha, G. E. (2023) · Neurochemical Research · doi:10.1007/s11064-023-03981-1 · Cited by 45 · see citing works
“Remarkably, fibrinogen enhances the recruitment of peripheral monocytes and interaction with myelin-specific antigens [107].”
BackgroundWellman, S. M., Cambi, F., & Kozai, T. D. Y. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.08.046 · Cited by 41 · see citing works
“Fibrin signaling also provokes T cell differentiation toward myelin antigen-specific Th1 cells via upregulation of IL-12 [178].”
Lv, K., Yuan, Q., Fu, P., Wu, G., Wu, X., Du, Z., Yu, J., Li, Z., & Hu, J. (2020) · World Journal of Emergency Surgery · doi:10.1186/s13017-020-00332-1 · Cited by 43 · see citing works
Lee, W., Milewski, T. M., Dwortz, M. F., Young, R. L., Gaudet, A. D., Fonken, L. K., Champagne, F. A., & Curley, J. P. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.04.015 · Cited by 42 · see citing works
Sun, Z., Zhao, H., Fang, D., Davis, C. T., Shi, D., Lei, K., Rich, B. E., Winter, J. M., Guo, L., Sorensen, L. K., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.07.015 · Cited by 42 · see citing works
“, 2002) that contribute to a hostile CNS environment and promote demyelination both by inducing the recruitment of peripheral inflammatory macrophages/monocytes and T cells and by inhibiting oligodendrocyte-mediated remyelination (Adams et al., 2007; Akassoglou et al., 2002; Davalos et al., 2012; Petersen et al., 2017…”
Chronic kidney disease promotes cerebral microhemorrhage formation
Fang, C., Lau, W. L., Sun, J., Chang, R., Vallejo, A., Lee, D., Liu, J., Liu, H., Hung, Y., Zhao, Y., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02703-2 · Cited by 40 · see citing works
“Fibrinogen/fibrin deposition is associated with microglial activation and increased immune cell recruitment into the brain [54, 58].”
BackgroundLiu, Y., Xue, M., Han, Y., Li, Y., Xiao, B., Wang, W., Yu, J., & Ye, X. (2023) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10500 · Cited by 38 · see citing works
“37,38 Briefly, BMDMs were extracted from the tibia and femur of 8-week-old Sprague – Dawley rats and cultured in RPMI-1640 (Gibco) medium supplemented with 10% fetal bovine serum (Gibco), 1% penicillin – streptomycin (Gibco), and 10 ng/mL rat M-CSF (Peprotech) in vitro.”
MethodLee, M. J., Jang, Y., Han, J., Kim, S. J., Ju, X., Lee, Y. L., Cui, J., Zhu, J., Ryu, M. J., Choi, S., et al. (2020) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x19900030 · Cited by 39 · see citing works
“Leakage of a plasma protein promotes chemokine release and T cell recruitment and demyelination.(40) However, the analysis of slides prepared from endoxifen-injected VECad Cre-ER-Crif1 mice revealed that CD45þ cells were scarce owing to the short observation period.”
BackgroundShaw, M. A., Gao, Z., McElhinney, K. E., Thornton, S., Flick, M. J., Lane, A., Degen, J. L., Ryu, J. K., Akassoglou, K., & Mullins, E. S. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2932-15.2017 · Cited by 38 · see citing works
“In this latter context, fibrin matrices appear to drive microglial/macrophage migration and local activation events, leading to demyelination and loss of motor function in EAE (Adams et al., 2007; Davalos et al., 2012; Ryu et al., 2015).”
BackgroundSelf-citationLi, S., Ju, Y., Zhou, J., Faria, M., Ang, C., Mitchell, A. J., Zhong, Q., Zheng, T., Kent, S. J., & Caruso, F. (2022) · Journal of Materials Chemistry B · doi:10.1039/d2tb00672c · Cited by 37 · see citing works
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“…and impairment of the BBB (Brightman, Klatzo, Olsson, & Reese, 1970; Petersen, Ryu, & Akassoglou, 2018), which contributes to neuroinflammation and autoimmune disorders such as Alzheimer's disease, Parkinson disease, and multiple sclerosis (Bennett et al., 2010; Ryu et al., 2015; Zlokovic, 2008).”
Vascular aspects of multiple sclerosis: emphasis on perfusion and cardiovascular comorbidities
Jakimovski, D., Topolski, M., Genovese, A. V., Weinstock‐Guttman, B., & Zivadinov, R. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1610394 · Cited by 35 · see citing works
“Fibrinogen can specifically activate both the adaptive and innate immune system and contribute to additional inflammatory demyelination [145].”
BackgroundFibrinogen, Fibrinogen-like 1 and Fibrinogen-like 2 Proteins, and Their Effects
Sulimai, N., Brown, J., & Lominadze, D. G. (2022) · Biomedicines · doi:10.3390/biomedicines10071712 · Cited by 38 · see citing works
In VivoImaging of CNS Injury and Disease
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“Using in vivo imaging in animal models of neuroimmunology and neurovascular dysfunction provides invaluable insight for the identification of molecular targets that could be instrumental for the development of novel therapeutic strategies, imaging probes, animal models, and biomarkers for disease onset and progression…”
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“The appearance of these fibrin plaques and the inflammatory cells that infiltrate the brain after a breach of the BBB is then associated with demyelination and neuronal dysfunction observed in these neurodegenerative diseases [12,107,108] (see Figure 2).”
BackgroundFibrinogen/AKT/Microfilament Axis Promotes Colitis by Enhancing Vascular Permeability
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“In the central nervous system, Fg promotes autoimmunity and demyelination via chemokine release and antigen presentation.(12) In addition, Fg promotes inflammation by activating monocytes via CD11b/CD18 receptors.”
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- Authors
- Ryu, J. K., Petersen, M. A., Murray, S. G., Baeten, K. M., Meyer-Franke, A., Chan, J. P., Vagena, E., Bedard, C., Machado, M. R., Coronado, P. E. R., Prod'homme, T., Charo, I. F., Lassmann, H., Degen, J. L., Zamvil, S. S., & Akassoglou, K.
- Affiliations
- University of California, San Francisco (US)
- Medical University of Vienna (AT)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Zamvil, Scott S.
- Akassoglou, Katerina
- ORCID
- Venue
- Nature Communications
- Published
- 2015-09-10
- Volume
- 6
- Issue
- 1
- Pages
- 8164-8164
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4579523
- OpenAlex
- W2257620318
- Cited by
- 271
- References
- 64
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 28 · 2023: 32 · 2022: 30 · 2021: 27 · 2020: 26 · 2019: 26 · 2018: 33 · 2017: 23 · 2016: 19 · 2015: 2
- FWCI
- 20.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Multiple Sclerosis Society (RG4768, RG4985)
- American Heart Association
- Multiple Sclerosis Society
- H. Lundbeck A/S
- National Institutes of Health (5k12hd072222-05, AI027763, CA082103)
- Center for AIDS Research, University of Washington (P30-AI027763)
- University of California, San Francisco (P30AI027763)
- National Heart, Lung, and Blood Institute (HL102475, HL096126, R01HL102475, R01HL096126)
- National Cancer Institute (CA-082103, P30CA082103)
- National Institute of Allergy and Infectious Diseases (R01AI073737, P30AI027763)
- National Institute of Neurological Disorders and Stroke (NS063008, NS052189, R01NS052189, R01NS063008)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12-HD072222, K12HD000850)
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- fibrinogen, central nervous system autoimmunity, demyelination, experimental autoimmune encephalomyelitis, multiple sclerosis, macrophage recruitment, antigen presentation, MHC class II, Th1 cells, myelin antigens, blood-brain barrier disruption, CXCL10, MCP-1, CD11b/CD18, fibrinogen receptor, neuroinflammation, chemokine signaling
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Blood-Brain Barrier, Brain, Demyelinating Diseases, DNA-Binding Proteins, Encephalomyelitis, Autoimmune, Experimental, Fibrin, Fibrinogen, Flow Cytometry, Genes, MHC Class II, Immunohistochemistry, Macrophages, Receptors, Antigen, T-Cell, Spinal Cord, Autoimmunity, Microglia, Antigen Presentation, Mice, Knockout, Homeodomain Proteins, Th1 Cells, Chemokines, Chemokine CCL2, Receptors, Chemokine, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, CD11b Antigen, Cell Proliferation, Mice, Rats, Chemokine CXCL10, Adaptive Immunity, Myelin-Oligodendrocyte Glycoprotein
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