The Interplay between Meningeal Lymphatic Vessels and
Neuroinflammation in Neurodegenerative Diseases

Junmei      Chen; Yaru      Pan; Qihua      Liu; Guangyao      Li; Gongcan      Chen; Weirong      Li; Wei      Zhao; Qi      Wang
doi:10.2174/1570159X21666221115150253
Abstract

Meningeal lymphatic vessels (MLVs) are essential for the drainage of cerebrospinal fluid, macromolecules, and immune cells in the central nervous system. They play critical roles in modulating neuroinflammation in neurodegenerative diseases. Dysfunctional MLVs have been demonstrated to increase neuroinflammation by horizontally blocking the drainage of neurotoxic proteins to the peripheral lymph nodes. Conversely, MLVs protect against neuroinflammation by preventing immune cells from becoming fully encephalitogenic. Furthermore, evidence suggests that neuroinflammation affects the structure and function of MLVs, causing vascular anomalies and angiogenesis. Although this field is still in its infancy, the strong link between MLVs and neuroinflammation has emerged as a potential target for slowing the progression of neurodegenerative diseases. This review provides a brief history of the discovery of MLVs, introduces in vivo and in vitro MLV models, highlights the molecular mechanisms through which MLVs contribute to and protect against neuroinflammation, and discusses the potential impact of neuroinflammation on MLVs, focusing on recent progress in neurodegenerative diseases.
Keywords: Meningeal lymphatic vessels, neuroinflammation, interplay, neurodegenerative diseases, neurodegeneration, interaction.
[1]
Louveau, A.; Smirnov, I.; Keyes, T.J.; Eccles, J.D.; Rouhani, S.J.; Peske, J.D.; Derecki, N.C.; Castle, D.; Mandell, J.W.; Lee, K.S.; Harris, T.H.; Kipnis, J. Structural and functional features of central nervous system lymphatic vessels. Nature,  2015, 523(7560), 337-341.
 [http://dx.doi.org/10.1038/nature14432] [PMID:  26030524]

[2]
Antila, S.; Karaman, S.; Nurmi, H.; Airavaara, M.; Voutilainen, M.H.; Mathivet, T.; Chilov, D.; Li, Z.; Koppinen, T.; Park, J.H.; Fang, S.; Aspelund, A.; Saarma, M.; Eichmann, A.; Thomas, J.L.; Alitalo, K. Development and plasticity of meningeal lymphatic vessels. J. Exp. Med.,  2017, 214(12), 3645-3667.
 [http://dx.doi.org/10.1084/jem.20170391] [PMID:  29141865]

[3]
Da Mesquita, S.; Louveau, A.; Vaccari, A.; Smirnov, I.; Cornelison, R.C.; Kingsmore, K.M.; Contarino, C.; Onengut-Gumuscu, S.; Farber, E.; Raper, D.; Viar, K.E.; Powell, R.D.; Baker, W.; Dabhi, N.; Bai, R.; Cao, R.; Hu, S.; Rich, S.S.; Munson, J.M.; Lopes, M.B.; Overall, C.C.; Acton, S.T.; Kipnis, J. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature,  2018, 560(7717), 185-191.
 [http://dx.doi.org/10.1038/s41586-018-0368-8] [PMID:  30046111]

[4]
Da Mesquita, S.; Fu, Z.; Kipnis, J. The meningeal lymphatic system: A new player in neurophysiology. Neuron,  2018, 100(2), 375-388.
 [http://dx.doi.org/10.1016/j.neuron.2018.09.022] [PMID:  30359603]

[5]
Aspelund, A.; Antila, S.; Proulx, S.T.; Karlsen, T.V.; Karaman, S.; Detmar, M.; Wiig, H.; Alitalo, K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med.,  2015, 212(7), 991-999.
 [http://dx.doi.org/10.1084/jem.20142290] [PMID:  26077718]

[6]
Ahn, J.H.; Cho, H.; Kim, J.H.; Kim, S.H.; Ham, J.S.; Park, I.; Suh, S.H.; Hong, S.P.; Song, J.H.; Hong, Y.K.; Jeong, Y.; Park, S.H.; Koh, G.Y. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature,  2019, 572(7767), 62-66.
 [http://dx.doi.org/10.1038/s41586-019-1419-5] [PMID:  31341278]

[7]
Sweeney, M.D.; Zlokovic, B.V. A lymphatic waste-disposal system implicated in Alzheimer’s disease. Nature,  2018, 560(7717), 172-174.
 [http://dx.doi.org/10.1038/d41586-018-05763-0] [PMID:  30076374]

[8]
Wang, L.; Zhang, Y.; Zhao, Y.; Marshall, C.; Wu, T.; Xiao, M. Deep cervical lymph node ligation aggravates AD-like pathology of APP/PS1 mice. Brain Pathol.,  2019, 29(2), 176-192.
 [http://dx.doi.org/10.1111/bpa.12656] [PMID:  30192999]

[9]
Patel, T.K.; Habimana-Griffin, L.; Gao, X.; Xu, B.; Achilefu, S.; Alitalo, K.; McKee, C.A.; Sheehan, P.W.; Musiek, E.S.; Xiong, C.; Coble, D.; Holtzman, D.M. Dural lymphatics regulate clearance of extracellular tau from the CNS. Mol. Neurodegener.,  2019, 14(1), 11.
 [http://dx.doi.org/10.1186/s13024-019-0312-x] [PMID:  30813965]

[10]
Zou, W.; Pu, T.; Feng, W.; Lu, M.; Zheng, Y.; Du, R.; Xiao, M.; Hu, G. Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated α-synuclein. Transl. Neurodegener.,  2019, 8(1), 7.
 [http://dx.doi.org/10.1186/s40035-019-0147-y] [PMID:  30867902]

[11]
Louveau, A.; Herz, J.; Alme, M.N.; Salvador, A.F.; Dong, M.Q.; Viar, K.E.; Herod, S.G.; Knopp, J.; Setliff, J.C.; Lupi, A.L.; Da Mesquita, S.; Frost, E.L.; Gaultier, A.; Harris, T.H.; Cao, R.; Hu, S.; Lukens, J.R.; Smirnov, I.; Overall, C.C.; Oliver, G.; Kipnis, J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat. Neurosci.,  2018, 21(10), 1380-1391.
 [http://dx.doi.org/10.1038/s41593-018-0227-9] [PMID:  30224810]

[12]
Yanev, P.; Poinsatte, K.; Hominick, D.; Khurana, N.; Zuurbier, K.R.; Berndt, M.; Plautz, E.J.; Dellinger, M.T.; Stowe, A.M. Impaired meningeal lymphatic vessel development worsens stroke outcome. J. Cereb. Blood Flow Metab.,  2020, 40(2), 263-275.
 [http://dx.doi.org/10.1177/0271678X18822921] [PMID:  30621519]

[13]
Chen, J.; He, J.; Ni, R.; Yang, Q.; Zhang, Y.; Luo, L. Cerebrovascular Injuries Induce Lymphatic Invasion into Brain Parenchyma to Guide Vascular Regeneration in Zebrafish. Dev. Cell,  2019, 49(5), 697-710.e5.
 [http://dx.doi.org/10.1016/j.devcel.2019.03.022] [PMID:  31006646]

[14]
Esposito, E.; Ahn, B.J.; Shi, J.; Nakamura, Y.; Park, J.H.; Mandeville, E.T.; Yu, Z.; Chan, S.J.; Desai, R.; Hayakawa, A.; Ji, X.; Lo, E.H.; Hayakawa, K. Brain-to-cervical lymph node signaling after stroke. Nat. Commun.,  2019, 10(1), 5306.
 [http://dx.doi.org/10.1038/s41467-019-13324-w] [PMID:  31757960]

[15]
Chachaj, A.; Gąsiorowski, K.; Szuba, A.; Sieradzki, A.; Leszek, J. Lymphatic system in the brain clearance mechanisms - new therapeutic perspectives for Alzheimer’s disease. Curr. Neuropharmacol.,  2023, 21(2), 380-391.
 [http://dx.doi.org/10.2174/1570159X20666220411091332] [PMID:  35410605]

[16]
Nikolenko, V.N.; Oganesyan, M.V.; Vovkogon, A.D.; Nikitina, A.T.; Sozonova, E.A.; Kudryashova, V.A.; Rizaeva, N.A.; Cabezas, R.; Avila-Rodriguez, M.; Neganova, M.E.; Mikhaleva, L.M.; Bachurin, S.O.; Somasundaram, S.G.; Kirkland, C.E.; Tarasov, V.V.; Aliev, G. Current understanding of central nervous system drainage systems: Implications in the context of neurodegenerative diseases. Curr. Neuropharmacol.,  2020, 18(11), 1054-1063.
 [http://dx.doi.org/10.2174/1570159X17666191113103850] [PMID:  31729299]

[17]
Guzman-Martinez, L.; Maccioni, R.B.; Andrade, V.; Navarrete, L.P.; Pastor, M.G.; Ramos-Escobar, N. Neuroinflammation as a common feature of neurodegenerative disorders. Front. Pharmacol.,  2019, 10, 1008.
 [http://dx.doi.org/10.3389/fphar.2019.01008] [PMID:  31572186]

[18]
Ransohoff, R.M. How neuroinflammation contributes to neurodegeneration. Science,  2016, 353(6301), 777-783.
 [http://dx.doi.org/10.1126/science.aag2590] [PMID:  27540165]

[19]
Beuker, C.; Schafflick, D.; Strecker, J.K.; Heming, M.; Li, X.; Wolbert, J.; Schmidt-Pogoda, A.; Thomas, C.; Kuhlmann, T.; Aranda-Pardos, I. A-Gonzalez, N.; Kumar, P.A.; Werner, Y.; Kilic, E.; Hermann, D.M.; Wiendl, H.; Stumm, R.; Meyer zu Hörste, G.; Minnerup, J. Stroke induces disease-specific myeloid cells in the brain parenchyma and pia. Nat. Commun.,  2022, 13(1), 945.
 [http://dx.doi.org/10.1038/s41467-022-28593-1] [PMID:  35177618]

[20]
Kwon, H.S.; Koh, S.H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl. Neurodegener.,  2020, 9(1), 42.
 [http://dx.doi.org/10.1186/s40035-020-00221-2] [PMID:  33239064]

[21]
Minoretti, P.; Gazzaruso, C.; Vito, C.D.; Emanuele, E.; Bianchi, M.; Coen, E.; Reino, M.; Geroldi, D. Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer’s disease. Neurosci. Lett.,  2006, 391(3), 147-149.
 [http://dx.doi.org/10.1016/j.neulet.2005.08.047] [PMID:  16157451]

[22]
Simon, D.K.; Simuni, T.; Elm, J.; Clark-Matott, J.; Graebner, A.K.; Baker, L.; Dunlop, S.R.; Emborg, M.; Kamp, C.; Morgan, J.C.; Ross, G.W.; Sharma, S.; Ravina, B. Peripheral biomarkers of Parkinson’s disease progression and pioglitazone effects. J. Parkinsons Dis.,  2015, 5(4), 731-736.
 [http://dx.doi.org/10.3233/JPD-150666] [PMID:  26444095]

[23]
Hossain, M.J.; Morandi, E.; Tanasescu, R.; Frakich, N.; Caldano, M.; Onion, D.; Faraj, T.A.; Erridge, C.; Gran, B. The soluble form of toll-like receptor 2 is elevated in serum of multiple sclerosis patients: A novel potential disease biomarker. Front. Immunol.,  2018, 9, 457.
 [http://dx.doi.org/10.3389/fimmu.2018.00457] [PMID:  29593720]

[24]
Comabella, M.; Pericot, I.; Goertsches, R.; Nos, C.; Castillo, M.; Blas, N.J.; Río, J.; Montalban, X. Plasma osteopontin levels in multiple sclerosis. J. Neuroimmunol.,  2005, 158(1-2), 231-239.
 [http://dx.doi.org/10.1016/j.jneuroim.2004.09.004] [PMID:  15589058]

[25]
Chen, J.; Wang, L.; Xu, H.; Xing, L.; Zhuang, Z.; Zheng, Y.; Li, X.; Wang, C.; Chen, S.; Guo, Z.; Liang, Q.; Wang, Y. Meningeal lymphatics clear erythrocytes that arise from subarachnoid hemorrhage. Nat. Commun.,  2020, 11(1), 3159.
 [http://dx.doi.org/10.1038/s41467-020-16851-z] [PMID:  32572022]

[26]
Da Mesquita, S.; Papadopoulos, Z.; Dykstra, T.; Brase, L.; Farias, F.G.; Wall, M.; Jiang, H.; Kodira, C.D.; de Lima, K.A.; Herz, J.; Louveau, A.; Goldman, D.H.; Salvador, A.F.; Onengut-Gumuscu, S.; Farber, E.; Dabhi, N.; Kennedy, T.; Milam, M.G.; Baker, W.; Smirnov, I.; Rich, S.S.; Benitez, B.A.; Karch, C.M.; Perrin, R.J.; Farlow, M.; Chhatwal, J.P.; Holtzman, D.M.; Cruchaga, C.; Harari, O.; Kipnis, J. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature,  2021, 593(7858), 255-260.
 [http://dx.doi.org/10.1038/s41586-021-03489-0] [PMID:  33911285]

[27]
Raper, D.; Louveau, A.; Kipnis, J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci.,  2016, 39(9), 581-586.
 [http://dx.doi.org/10.1016/j.tins.2016.07.001] [PMID:  27460561]

[28]
Dá Mesquita, S.; Ferreira, A.C.; Sousa, J.C.; Correia-Neves, M.; Sousa, N.; Marques, F. Insights on the pathophysiology of Alzheimer’s disease: The crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci. Biobehav. Rev.,  2016, 68, 547-562.
 [http://dx.doi.org/10.1016/j.neubiorev.2016.06.014] [PMID:  27328788]

[29]
Hsu, S.J.; Zhang, C.; Jeong, J.; Lee, S.; McConnell, M.; Utsumi, T.; Iwakiri, Y. Enhanced meningeal lymphatic drainage ameliorates neuroinflammation and hepatic encephalopathy in cirrhotic rats. Gastroenterology,  2021, 160(4), 1315-1329.e13.
 [http://dx.doi.org/10.1053/j.gastro.2020.11.036] [PMID:  33227282]

[30]
He, X.; Li, L.; Xian, W.; Li, M.; Zhang, L.; Xu, J.; Pei, Z.; Zheng, H.; Hu, X. Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain. J. Neuroinflammation,  2021, 18(1), 153.
 [http://dx.doi.org/10.1186/s12974-021-02199-8] [PMID:  34229722]

[31]
Wojciechowski, S.; Virenque, A.; Vihma, M.; Galbardi, B.; Rooney, E.J.; Keuters, M.H.; Antila, S.; Koistinaho, J.; Noe, F.M. Developmental dysfunction of the central nervous system lymphatics modulates the adaptive neuro-immune response in the perilesional cortex in a mouse model of traumatic brain injury. Front. Immunol.,  2021, 11, 559810.
 [http://dx.doi.org/10.3389/fimmu.2020.559810] [PMID:  33584640]

[32]
Song, E.; Mao, T.; Dong, H.; Boisserand, L.S.B.; Antila, S.; Bosenberg, M.; Alitalo, K.; Thomas, J.L.; Iwasaki, A. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature,  2020, 577(7792), 689-694.
 [http://dx.doi.org/10.1038/s41586-019-1912-x] [PMID:  31942068]

[33]
das Neves, S.P.; Delivanoglou, N.; Da Mesquita, S. CNS-draining meningeal lymphatic vasculature: Roles, conundrums and future challenges. Front. Pharmacol.,  2021, 12, 655052.
 [http://dx.doi.org/10.3389/fphar.2021.655052] [PMID:  33995074]

[34]
Mogensen, F.L.H.; Delle, C.; Nedergaard, M. The glymphatic system (En)during inflammation. Int. J. Mol. Sci.,  2021, 22(14), 7491.
 [http://dx.doi.org/10.3390/ijms22147491] [PMID:  34299111]

[35]
Hsu, M.; Laaker, C.; Sandor, M.; Fabry, Z. Neuroinflammation-driven lymphangiogenesis in CNS diseases. Front. Cell. Neurosci.,  2021, 15, 683676.
 [http://dx.doi.org/10.3389/fncel.2021.683676] [PMID:  34248503]

[36]
Tavares, G.A.; Louveau, A. Meningeal lymphatics: An immune gateway for the central nervous system. Cells,  2021, 10(12), 3385.
 [http://dx.doi.org/10.3390/cells10123385] [PMID:  34943894]

[37]
Bucchieri, F.; Farina, F.; Zummo, G.; Cappello, F. Lymphatic vessels of the dura mater: a new discovery? J. Anat.,  2015, 227(5), 702-703.
 [http://dx.doi.org/10.1111/joa.12381] [PMID:  26383824]

[38]
Lecco, V. Probable modification of the lymphatic fissures of the walls of the venous sinuses of the dura mater. Arch. Ital. Otol. Rinol. Laringol.,  1953, 64(3), 287-296.
 [PMID:  13081359]

[39]
Földi, M.; Gellért, A.; Kozma, M.; Poberai, M.; Zoltán, Ö.T.; Csanda, E. New contributions to the anatomical connections of the brain and the lymphatic system. Cells Tissues Organs,  1966, 64(4), 498-505.
 [http://dx.doi.org/10.1159/000142849] [PMID:  5957959]

[40]
Andres, K.H.; von Düring, M.; Muszynski, K.; Schmidt, R.F. Nerve fibres and their terminals of the dura mater encephali of the rat. Anat. Embryol. (Berl.),  1987, 175(3), 289-301.
 [http://dx.doi.org/10.1007/BF00309843] [PMID:  3826655]

[41]
Li, J.; Zhou, J.; Shi, Y. Scanning electron microscopy of human cerebral meningeal stomata. Ann. Anat.,  1996, 178(3), 259-261.
 [http://dx.doi.org/10.1016/S0940-9602(96)80059-8] [PMID:  8712374]

[42]
Sun, B.L.; Xia, Z.L.; Wang, J.R.; Yuan, H.; Li, W.X.; Chen, Y.S.; Yang, M.F.; Zhang, S.M. Effects of blockade of cerebral lymphatic drainage on regional cerebral blood flow and brain edema after subarachnoid hemorrhage. Clin. Hemorheol. Microcirc.,  2006, 34(1-2), 227-232.
 [PMID:  16543641]

[43]
Sun, B.L.; Xia, Z.L.; Yan, Z.W.; Chen, Y.S.; Yang, M.F. Effects of blockade of cerebral lymphatic drainage on cerebral ischemia after middle cerebral artery occlusion in rats. Clin. Hemorheol. Microcirc.,  2000, 23(2-4), 321-325.
 [PMID:  11321458]

[44]
Si, J.; Chen, L.; Xia, Z. Effects of cervical-lymphatic blockade on brain edema and infarction volume in cerebral ischemic rats. Chin. J. Physiol.,  2006, 49(5), 258-265.
 [PMID:  17294834]

[45]
Sun, B.; Xie, F.; Yang, M.; Cao, M.; Yuan, H.; Wang, H.; Wang, J.; Jia, L. Blocking cerebral lymphatic drainage deteriorates cerebral oxidative injury in rats with subarachnoid hemorrhage. Acta Neurochir. Suppl. (Wien),  2011, 110(Pt 2), 49-53.
 [http://dx.doi.org/10.1007/978-3-7091-0356-2_10] [PMID:  21125445]

[46]
Absinta, M.; Ha, S.K.; Nair, G.; Sati, P.; Luciano, N.J.; Palisoc, M.; Louveau, A.; Zaghloul, K.A.; Pittaluga, S.; Kipnis, J.; Reich, D.S. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife,  2017, 6, e29738.
 [http://dx.doi.org/10.7554/eLife.29738] [PMID:  28971799]

[47]
Wu, C.H.; Lirng, J.F.; Ling, Y.H.; Wang, Y.F.; Wu, H.M.; Fuh, J.L.; Lin, P.C.; Wang, S.J.; Chen, S.P. Noninvasive characterization of human glymphatics and meningeal lymphatics in an in vivo model of blood-brain barrier leakage. Ann. Neurol.,  2021, 89(1), 111-124.
 [http://dx.doi.org/10.1002/ana.25928] [PMID:  33030257]

[48]
Yao, Z-B.; Wen, Y-R.; Yang, J-H.; Wang, X. Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer’s disease. Neural Regen. Res.,  2018, 13(4), 709-716.
 [http://dx.doi.org/10.4103/1673-5374.230299] [PMID:  29722325]

[49]
Ringstad, G.; Eide, P.K. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat. Commun.,  2020, 11(1), 354.
 [http://dx.doi.org/10.1038/s41467-019-14195-x] [PMID:  31953399]

[50]
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.; Lammert, C.R.; Kipnis, J.; Lukens, J.R. Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis. Nat. Commun.,  2020, 11(1), 4524.
 [http://dx.doi.org/10.1038/s41467-020-18113-4] [PMID:  32913280]

[51]
Shimada, R.; Tatara, Y.; Kibayashi, K. Gene expression in meningeal lymphatic endothelial cells following traumatic brain injury in mice. PLoS One,  2022, 17(9), e0273892.
 [http://dx.doi.org/10.1371/journal.pone.0273892] [PMID:  36067135]

[52]
Castranova, D.; Samasa, B.; Venero, G.M.; Jung, H.M.; Pham, V.N.; Weinstein, B.M. Live imaging of intracranial lymphatics in the zebrafish. Circ. Res.,  2021, 128(1), 42-58.
 [http://dx.doi.org/10.1161/CIRCRESAHA.120.317372] [PMID:  33135960]

[53]
Mezey, É.; Szalayova, I.; Hogden, C.T.; Brady, A.; Dósa, Á.; Sótonyi, P.; Palkovits, M. An immunohistochemical study of lymphatic elements in the human brain. Proc. Natl. Acad. Sci. USA,  2021, 118(3), e2002574118.
 [http://dx.doi.org/10.1073/pnas.2002574118] [PMID:  33446503]

[54]
Ding, X.B.; Wang, X.X.; Xia, D.H.; Liu, H.; Tian, H.Y.; Fu, Y.; Chen, Y.K.; Qin, C.; Wang, J.Q.; Xiang, Z.; Zhang, Z.X.; Cao, Q.C.; Wang, W.; Li, J.Y.; Wu, E.; Tang, B.S.; Ma, M.M.; Teng, J.F.; Wang, X.J. Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease. Nat. Med.,  2021, 27(3), 411-418.
 [http://dx.doi.org/10.1038/s41591-020-01198-1] [PMID:  33462448]

[55]
Hsu, M.; Laaker, C.; Madrid, A.; Herbath, M.; Choi, Y.H.; Sandor, M.; Fabry, Z. Neuroinflammation creates an immune regulatory niche at the meningeal lymphatic vasculature near the cribriform plate. Nat. Immunol.,  2022, 23(4), 581-593.
 [http://dx.doi.org/10.1038/s41590-022-01158-6] [PMID:  35347285]

[56]
Li, Q.; Chen, Y.; Feng, W.; Cai, J.; Gao, J.; Ge, F.; Zhou, T.; Wang, Z.; Ding, F.; Marshall, C.; Sheng, C.; Zhang, Y.; Sun, M.; Shi, J.; Xiao, M. Drainage of senescent astrocytes from brain via meningeal lymphatic routes. Brain Behav. Immun.,  2022, 103, 85-96.
 [http://dx.doi.org/10.1016/j.bbi.2022.04.005] [PMID:  35427759]

[57]
Li, X.; Qi, L.; Yang, D.; Hao, S.; Zhang, F.; Zhu, X.; Sun, Y.; Chen, C.; Ye, J.; Yang, J.; Zhao, L.; Altmann, D.M.; Cao, S.; Wang, H.; Wei, B. Meningeal lymphatic vessels mediate neurotropic viral drainage from the central nervous system. Nat. Neurosci.,  2022, 25(5), 577-587.
 [http://dx.doi.org/10.1038/s41593-022-01063-z] [PMID:  35524140]

[58]
Jacob, L.; Boisserand, L.S.B.; Geraldo, L.H.M.; de Brito Neto, J.; Mathivet, T.; Antila, S.; Barka, B.; Xu, Y.; Thomas, J.M.; Pestel, J.; Aigrot, M.S.; Song, E.; Nurmi, H.; Lee, S.; Alitalo, K.; Renier, N.; Eichmann, A.; Thomas, J.L. Anatomy and function of the vertebral column lymphatic network in mice. Nat. Commun.,  2019, 10(1), 4594.
 [http://dx.doi.org/10.1038/s41467-019-12568-w] [PMID:  31597914]

[59]
Elham, E.; Wumaier, R.; Wang, C.; Luo, X.; Chen, T.; Zhong, N. Anatomic evidence shows that lymphatic drainage exists in the pituitary to loop the cerebral lymphatic circulation. Med. Hypotheses,  2020, 143, 109898.
 [http://dx.doi.org/10.1016/j.mehy.2020.109898] [PMID:  32504926]

[60]
Shibata-Germanos, S.; Goodman, J.R.; Grieg, A.; Trivedi, C.A.; Benson, B.C.; Foti, S.C.; Faro, A.; Castellan, R.F.P.; Correra, R.M.; Barber, M.; Ruhrberg, C.; Weller, R.O.; Lashley, T.; Iliff, J.J.; Hawkins, T.A.; Rihel, J. Structural and functional conservation of non-lumenized lymphatic endothelial cells in the mammalian leptomeninges. Acta Neuropathol.,  2020, 139(2), 383-401.
 [http://dx.doi.org/10.1007/s00401-019-02091-z] [PMID:  31696318]

[61]
Albayram, M.S.; Smith, G.; Tufan, F.; Tuna, I.S.; Bostancıklıoğlu, M.; Zile, M.; Albayram, O. Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes. Nat. Commun.,  2022, 13(1), 203.
 [http://dx.doi.org/10.1038/s41467-021-27887-0] [PMID:  35017525]

[62]
Rasmussen, M.K.; Mestre, H.; Nedergaard, M. The glymphatic pathway in neurological disorders. Lancet Neurol.,  2018, 17(11), 1016-1024.
 [http://dx.doi.org/10.1016/S1474-4422(18)30318-1] [PMID:  30353860]

[63]
Zhou, Y.; Cai, J.; Zhang, W.; Gong, X.; Yan, S.; Zhang, K.; Luo, Z.; Sun, J.; Jiang, Q.; Lou, M. Impairment of the glymphatic pathway and putative meningeal lymphatic vessels in the aging human. Ann. Neurol.,  2020, 87(3), 357-369.
 [http://dx.doi.org/10.1002/ana.25670] [PMID:  31916277]

[64]
Cheng, Y.; Tian, D.Y.; Wang, Y.J. Peripheral clearance of brain-derived Aβ in Alzheimer’s disease: pathophysiology and therapeutic perspectives. Transl. Neurodegener.,  2020, 9(1), 16.
 [http://dx.doi.org/10.1186/s40035-020-00195-1] [PMID:  32381118]

[65]
Ma, Q.; Ineichen, B.V.; Detmar, M.; Proulx, S.T. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat. Commun.,  2017, 8(1), 1434.
 [http://dx.doi.org/10.1038/s41467-017-01484-6] [PMID:  29127332]

[66]
Brady, M.; Rahman, A.; Combs, A.; Venkatraman, C.; Kasper, R.T.; McQuaid, C.; Kwok, W.C.E.; Wood, R.W.; Deane, R. Cerebrospinal fluid drainage kinetics across the cribriform plate are reduced with aging. Fluids Barriers CNS,  2020, 17(1), 71.
 [http://dx.doi.org/10.1186/s12987-020-00233-0] [PMID:  33256800]

[67]
Schafflick, D.; Wolbert, J.; Heming, M.; Thomas, C.; Hartlehnert, M.; Börsch, A.L.; Ricci, A.; Martín-Salamanca, S.; Li, X.; Lu, I.N.; Pawlak, M.; Minnerup, J.; Strecker, J.K.; Seidenbecher, T.; Meuth, S.G.; Hidalgo, A.; Liesz, A.; Wiendl, H.; Meyer zu Horste, G. Single-cell profiling of CNS border compartment leukocytes reveals that B cells and their progenitors reside in non-diseased meninges. Nat. Neurosci.,  2021, 24(9), 1225-1234.
 [http://dx.doi.org/10.1038/s41593-021-00880-y] [PMID:  34253922]

[68]
Van Hove, H.; Martens, L.; Scheyltjens, I.; De Vlaminck, K.; Pombo Antunes, A.R.; De Prijck, S.; Vandamme, N.; De Schepper, S.; Van Isterdael, G.; Scott, C.L.; Aerts, J.; Berx, G.; Boeckxstaens, G.E.; Vandenbroucke, R.E.; Vereecke, L.; Moechars, D.; Guilliams, M.; Van Ginderachter, J.A.; Saeys, Y.; Movahedi, K. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci.,  2019, 22(6), 1021-1035.
 [http://dx.doi.org/10.1038/s41593-019-0393-4] [PMID:  31061494]

[69]
McMenamin, P.G. Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. J. Comp. Neurol.,  1999, 405(4), 553-562.
 [http://dx.doi.org/10.1002/(SICI)1096-9861(19990322)405:4<553:AID-CNE8>3.0.CO;2-6] [PMID:  10098945]

[70]
Rustenhoven, J.; Drieu, A.; Mamuladze, T.; de Lima, K.A.; Dykstra, T.; Wall, M.; Papadopoulos, Z.; Kanamori, M.; Salvador, A.F.; Baker, W.; Lemieux, M.; Da Mesquita, S.; Cugurra, A.; Fitzpatrick, J.; Sviben, S.; Kossina, R.; Bayguinov, P.; Townsend, R.R.; Zhang, Q.; Erdmann-Gilmore, P.; Smirnov, I.; Lopes, M.B.; Herz, J.; Kipnis, J. Functional characterization of the dural sinuses as a neuroimmune interface. Cell,  2021, 184(4), 1000-1016.e27.
 [http://dx.doi.org/10.1016/j.cell.2020.12.040] [PMID:  33508229]

[71]
Fitzpatrick, Z.; Frazer, G.; Ferro, A.; Clare, S.; Bouladoux, N.; Ferdinand, J.; Tuong, Z.K.; Negro-Demontel, M.L.; Kumar, N.; Suchanek, O.; Tajsic, T.; Harcourt, K.; Scott, K.; Bashford-Rogers, R.; Helmy, A.; Reich, D.S.; Belkaid, Y.; Lawley, T.D.; McGavern, D.B.; Clatworthy, M.R. Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature,  2020, 587(7834), 472-476.
 [http://dx.doi.org/10.1038/s41586-020-2886-4] [PMID:  33149302]

[72]
Da Mesquita, S.; Herz, J.; Wall, M.; Dykstra, T.; de Lima, K.A.; Norris, G.T.; Dabhi, N.; Kennedy, T.; Baker, W.; Kipnis, J. Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology. Sci. Adv.,  2021, 7(21), eabe4601.
 [http://dx.doi.org/10.1126/sciadv.abe4601] [PMID:  34020948]

[73]
Hu, X.; Deng, Q.; Ma, L.; Li, Q.; Chen, Y.; Liao, Y.; Zhou, F.; Zhang, C.; Shao, L.; Feng, J.; He, T.; Ning, W.; Kong, Y.; Huo, Y.; He, A.; Liu, B.; Zhang, J.; Adams, R.; He, Y.; Tang, F.; Bian, X.; Luo, J. Meningeal lymphatic vessels regulate brain tumor drainage and immunity. Cell Res.,  2020, 30(3), 229-243.
 [http://dx.doi.org/10.1038/s41422-020-0287-8] [PMID:  32094452]

[74]
Hauser, M.A.; Legler, D.F. Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes. J. Leukoc. Biol.,  2016, 99(6), 869-882.
 [http://dx.doi.org/10.1189/jlb.2MR0815-380R] [PMID:  26729814]

[75]
Salem, A.; Alotaibi, M.; Mroueh, R.; Basheer, H.A.; Afarinkia, K. CCR7 as a therapeutic target in Cancer. Biochim. Biophys. Acta Rev. Cancer,  2021, 1875(1), 188499.
 [http://dx.doi.org/10.1016/j.bbcan.2020.188499] [PMID:  33385485]

[76]
Brandum, E.P.; Jørgensen, A.S.; Rosenkilde, M.M.; Hjortø, G.M. Dendritic cells and CCR7 expression: An important factor for autoimmune diseases, chronic inflammation, and cancer. Int. J. Mol. Sci.,  2021, 22(15), 8340.
 [http://dx.doi.org/10.3390/ijms22158340] [PMID:  34361107]

[77]
Merlini, A.; Haberl, M.; Strauß, J.; Hildebrand, L.; Genc, N.; Franz, J.; Chilov, D.; Alitalo, K.; Flügel-Koch, C.; Stadelmann, C.; Flügel, A.; Odoardi, F. Distinct roles of the meningeal layers in CNS autoimmunity. Nat. Neurosci.,  2022, 25(7), 887-899.
 [http://dx.doi.org/10.1038/s41593-022-01108-3] [PMID:  35773544]

[78]
Goodman, J.R.; Adham, Z.O.; Woltjer, R.L.; Lund, A.W.; Iliff, J.J. Characterization of dural sinus-associated lymphatic vasculature in human Alzheimer’s dementia subjects. Brain Behav. Immun.,  2018, 73, 34-40.
 [http://dx.doi.org/10.1016/j.bbi.2018.07.020] [PMID:  30055243]

[79]
Park, M.; Kim, J.W.; Ahn, S.J.; Cha, Y.J.; Suh, S.H. Aging is positively associated with peri-sinus lymphatic space volume: Assessment using 3T black-blood MRI. J. Clin. Med.,  2020, 9(10), 3353.
 [http://dx.doi.org/10.3390/jcm9103353] [PMID:  33086702]

[80]
Jacob, L.; de Brito Neto, J.; Lenck, S.; Corcy, C.; Benbelkacem, F.; Geraldo, L.H.; Xu, Y.; Thomas, J.M.; El Kamouh, M.R.; Spajer, M.; Potier, M.C.; Haik, S.; Kalamarides, M.; Stankoff, B.; Lehericy, S.; Eichmann, A.; Thomas, J.L. Conserved meningeal lymphatic drainage circuits in mice and humans. J. Exp. Med.,  2022, 219(8), e20220035.
 [http://dx.doi.org/10.1084/jem.20220035] [PMID:  35776089]

[81]
Correia, J.H.; Rodrigues, J.A.; Pimenta, S.; Dong, T.; Yang, Z. Photodynamic therapy review: Principles, photosensitizers, applications, and future directions. Pharmaceutics,  2021, 13(9), 1332.
 [http://dx.doi.org/10.3390/pharmaceutics13091332] [PMID:  34575408]

[82]
Scott, L.J.; Goa, K.L. Verteporfin. Drugs Aging,  2000, 16(2), 139-146.
 [http://dx.doi.org/10.2165/00002512-200016020-00005] [PMID:  10755329]

[83]
Furlan, C.; Berenbeim, J.A.; Dessent, C.E.H. Photoproducts of the photodynamic therapy agent verteporfin identified via laser interfaced mass spectrometry. Molecules,  2020, 25(22), 5280.
 [http://dx.doi.org/10.3390/molecules25225280] [PMID:  33198255]

[84]
Semyachkina-Glushkovskaya, O.; Chehonin, V.; Borisova, E.; Fedosov, I.; Namykin, A.; Abdurashitov, A.; Shirokov, A.; Khlebtsov, B.; Lyubun, Y.; Navolokin, N.; Ulanova, M.; Shushunova, N.; Khorovodov, A.; Agranovich, I.; Bodrova, A.; Sagatova, M.; Shareef, A.E.; Saranceva, E.; Iskra, T.; Dvoryatkina, M.; Zhinchenko, E.; Sindeeva, O.; Tuchin, V.; Kurths, J. Photodynamic opening of the blood-brain barrier and pathways of brain clearing. J. Biophotonics,  2018, 11(8), e201700287.
 [http://dx.doi.org/10.1002/jbio.201700287] [PMID:  29380947]

[85]
Zhao, P.; Le, Z.; Liu, L.; Chen, Y. Therapeutic delivery to the brain via the lymphatic vasculature. Nano Lett.,  2020, 20(7), 5415-5420.
 [http://dx.doi.org/10.1021/acs.nanolett.0c01806] [PMID:  32510957]

[86]
Li, M.; Jing, Y.; Wu, C.; Li, X.; Liang, F.; Li, G.; Dai, P.; Yu, H.; Pei, Z.; Xu, G.; Lan, Y. Continuous theta burst stimulation dilates meningeal lymphatic vessels by up-regulating VEGF-C in meninges. Neurosci. Lett.,  2020, 735, 135197.
 [http://dx.doi.org/10.1016/j.neulet.2020.135197] [PMID:  32590044]

[87]
Mäkinen, T.; Jussila, L.; Veikkola, T.; Karpanen, T.; Kettunen, M.I.; Pulkkanen, K.J.; Kauppinen, R.; Jackson, D.G.; Kubo, H.; Nishikawa, S.I.; Ylä-Herttuala, S.; Alitalo, K. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat. Med.,  2001, 7(2), 199-205.
 [http://dx.doi.org/10.1038/84651] [PMID:  11175851]

[88]
Rustenhoven, J.; Tanumihardja, C.; Kipnis, J. Cerebrovascular anomalies: Perspectives from immunology and cerebrospinal fluid Flow. Circ. Res.,  2021, 129(1), 174-194.
 [http://dx.doi.org/10.1161/CIRCRESAHA.121.318173] [PMID:  34166075]

[89]
González, A.; González-González, A.; Alonso-González, C.; Menéndez-Menéndez, J.; Martínez-Campa, C.; Cos, S. Melatonin inhibits angiogenesis in SH-SY5Y human neuroblastoma cells by downregulation of VEGF. Oncol. Rep.,  2017, 37(4), 2433-2440.
 [http://dx.doi.org/10.3892/or.2017.5446] [PMID:  28259965]

[90]
Wachowska, M.; Osiak, A.; Muchowicz, A.; Gabrysiak, M. Domagała, A.; Kilarski, W.W.; Golab, J. Investigation of cell death mechanisms in human lymphatic endothelial cells undergoing photodynamic therapy. Photodiagn. Photodyn. Ther.,  2016, 14, 57-65.
 [http://dx.doi.org/10.1016/j.pdpdt.2016.02.004] [PMID:  26868051]

[91]
Tammela, T.; Saaristo, A.; Holopainen, T.; Ylä-Herttuala, S.; Andersson, L.C.; Virolainen, S.; Immonen, I.; Alitalo, K. Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis. Sci. Transl. Med.,  2011, 3(69), 69ra11.
 [http://dx.doi.org/10.1126/scitranslmed.3001699] [PMID:  21307301]

[92]
Muchowicz, A.; Wachowska, M.; Stachura, J.; Tonecka, K.; Gabrysiak, M.; Wołosz, D.; Pilch, Z.; Kilarski, W.W.; Boon, L.; Klaus, T.J.; Golab, J. Inhibition of lymphangiogenesis impairs antitumour effects of photodynamic therapy and checkpoint inhibitors in mice. Eur. J. Cancer,  2017, 83, 19-27.
 [http://dx.doi.org/10.1016/j.ejca.2017.06.004] [PMID:  28709135]

[93]
Wei, C.; Li, X. The Role of Photoactivated and non-photoactivated verteporfin on tumor. Front. Pharmacol.,  2020, 11, 557429.
 [http://dx.doi.org/10.3389/fphar.2020.557429] [PMID:  33178014]

[94]
Hou, Y.; Le, V.N.H.; Clahsen, T.; Schneider, A.C.; Bock, F.; Cursiefen, C. Photodynamic therapy leads to time-dependent regression of pathologic corneal (lymph) angiogenesis and promotes high-risk corneal allograft survival. Invest. Ophthalmol. Vis. Sci.,  2017, 58(13), 5862-5869.
 [http://dx.doi.org/10.1167/iovs.17-22904] [PMID:  29145577]

[95]
Bucher, F.; Bi, Y.; Gehlsen, U.; Hos, D.; Cursiefen, C.; Bock, F. Regression of mature lymphatic vessels in the cornea by photodynamic therapy. Br. J. Ophthalmol.,  2014, 98(3), 391-395.
 [http://dx.doi.org/10.1136/bjophthalmol-2013-303887] [PMID:  24414403]

[96]
Nowak-Sliwinska, P.; van den Bergh, H.; Sickenberg, M.; Koh, A.H.C. Photodynamic therapy for polypoidal choroidal vasculopathy. Prog. Retin. Eye Res.,  2013, 37, 182-199.
 [http://dx.doi.org/10.1016/j.preteyeres.2013.09.003] [PMID:  24140257]

[97]
Solenov, E.; Watanabe, H.; Manley, G.T.; Verkman, A.S. Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am. J. Physiol. Cell Physiol.,  2004, 286(2), C426-C432.
 [http://dx.doi.org/10.1152/ajpcell.00298.2003] [PMID:  14576087]

[98]
Heo, J.; Meng, F.; Hua, S.Z. Contribution of aquaporins to cellular water transport observed by a microfluidic cell volume sensor. Anal. Chem.,  2008, 80(18), 6974-6980.
 [http://dx.doi.org/10.1021/ac8008498] [PMID:  18698799]

[99]
MacAulay, N. Molecular mechanisms of brain water transport. Nat. Rev. Neurosci.,  2021, 22(6), 326-344.
 [http://dx.doi.org/10.1038/s41583-021-00454-8] [PMID:  33846637]

[100]
Heneka, M.T.; Carson, M.J.; Khoury, J.E.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; Herrup, K.; Frautschy, S.A.; Finsen, B.; Brown, G.C.; Verkhratsky, A.; Yamanaka, K.; Koistinaho, J.; Latz, E.; Halle, A.; Petzold, G.C.; Town, T.; Morgan, D.; Shinohara, M.L.; Perry, V.H.; Holmes, C.; Bazan, N.G.; Brooks, D.J.; Hunot, S.; Joseph, B.; Deigendesch, N.; Garaschuk, O.; Boddeke, E.; Dinarello, C.A.; Breitner, J.C.; Cole, G.M.; Golenbock, D.T.; Kummer, M.P. Neuroinflammation in Alzheimer’s disease. Lancet Neurol.,  2015, 14(4), 388-405.
 [http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID:  25792098]

[101]
Wang, Q.; Liu, Y.; Zhou, J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl. Neurodegener.,  2015, 4(1), 19.
 [http://dx.doi.org/10.1186/s40035-015-0042-0] [PMID:  26464797]

[102]
Uddin, M.S.; Kabir, M.T.; Jalouli, M.; Rahman, M.A.; Jeandet, P.; Behl, T.; Alexiou, A.; Albadrani, G.M.; Abdel-Daim, M.M.; Perveen, A.; Ashraf, G.M. Neuroinflammatory signaling in the pathogenesis of Alzheimer’s disease. Curr. Neuropharmacol.,  2022, 20(1), 126-146.
 [http://dx.doi.org/10.2174/1570159X19666210826130210] [PMID:  34525932]

[103]
Boland, B.; Yu, W.H.; Corti, O.; Mollereau, B.; Henriques, A.; Bezard, E.; Pastores, G.M.; Rubinsztein, D.C.; Nixon, R.A.; Duchen, M.R.; Mallucci, G.R.; Kroemer, G.; Levine, B.; Eskelinen, E.L.; Mochel, F.; Spedding, M.; Louis, C.; Martin, O.R.; Millan, M.J. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat. Rev. Drug Discov.,  2018, 17(9), 660-688.
 [http://dx.doi.org/10.1038/nrd.2018.109] [PMID:  30116051]

[104]
Tang, Y.; Le, W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol. Neurobiol.,  2016, 53(2), 1181-1194.
 [http://dx.doi.org/10.1007/s12035-014-9070-5] [PMID:  25598354]

[105]
Alitalo, K.; Tammela, T.; Petrova, T.V. Lymphangiogenesis in development and human disease. Nature,  2005, 438(7070), 946-953.
 [http://dx.doi.org/10.1038/nature04480] [PMID:  16355212]

[106]
Secker, G.A.; Harvey, N.L. VEGFR signaling during lymphatic vascular development: From progenitor cells to functional vessels. Dev. Dyn.,  2015, 244(3), 323-331.
 [http://dx.doi.org/10.1002/dvdy.24227] [PMID:  25399804]

[107]
Lee, Y.G.; Koh, G.Y. Coordinated lymphangiogenesis is critical in lymph node development and maturation. Dev. Dyn.,  2016, 245(12), 1189-1197.
 [http://dx.doi.org/10.1002/dvdy.24456] [PMID:  27623309]

[108]
Deng, Y.; Zhang, X.; Simons, M. Molecular controls of lymphatic VEGFR3 signaling. Arterioscler. Thromb. Vasc. Biol.,  2015, 35(2), 421-429.
 [http://dx.doi.org/10.1161/ATVBAHA.114.304881] [PMID:  25524775]

[109]
Nava Catorce, M.; Gevorkian, G. LPS-induced murine neuroinflammation model: Main features and suitability for pre-clinical assessment of nutraceuticals. Curr. Neuropharmacol.,  2016, 14(2), 155-164.
 [http://dx.doi.org/10.2174/1570159X14666151204122017] [PMID:  26639457]

[110]
Qin, L.; Wu, X.; Block, M.L.; Liu, Y.; Breese, G.R.; Hong, J.S.; Knapp, D.J.; Crews, F.T. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia,  2007, 55(5), 453-462.
 [http://dx.doi.org/10.1002/glia.20467] [PMID:  17203472]

[111]
Park, S.H.; Kim, N.D.; Jung, J.K.; Lee, C.K.; Han, S.B.; Kim, Y. Myeloid differentiation 2 as a therapeutic target of inflammatory disorders. Pharmacol. Ther.,  2012, 133(3), 291-298.
 [http://dx.doi.org/10.1016/j.pharmthera.2011.11.001] [PMID:  22119168]

[112]
Holdbrook, D.A.; Huber, R.G.; Marzinek, J.K.; Stubbusch, A.; Schmidtchen, A.; Bond, P.J. Multiscale modeling of innate immune receptors: Endotoxin recognition and regulation by host defense peptides. Pharmacol. Res.,  2019, 147, 104372.
 [http://dx.doi.org/10.1016/j.phrs.2019.104372] [PMID:  31351116]

[113]
Manouchehrian, O.; Ramos, M.; Bachiller, S.; Lundgaard, I.; Deierborg, T. Acute systemic LPS-exposure impairs perivascular CSF distribution in mice. J. Neuroinflammation,  2021, 18(1), 34.
 [http://dx.doi.org/10.1186/s12974-021-02082-6] [PMID:  33514389]

[114]
Sun, B.L.; Wang, L.; Yang, T.; Sun, J.; Mao, L.; Yang, M.; Yuan, H.; Colvin, R.A.; Yang, X. Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases. Prog. Neurobiol.,  2018, 163-164, 118-143.
 [http://dx.doi.org/10.1016/j.pneurobio.2017.08.007] [PMID:  28903061]

[115]
Kim, H.; Kim, S.; Shin, S.J.; Park, Y.H.; Nam, Y.; Kim, C.; Lee, K.; Kim, S.M.; Jung, I.D.; Yang, H.D.; Park, Y.M.; Moon, M. Gram-negative bacteria and their lipopolysaccharides in Alzheimer’s disease: pathologic roles and therapeutic implications. Transl. Neurodegener.,  2021, 10(1), 49.
 [http://dx.doi.org/10.1186/s40035-021-00273-y] [PMID:  34876226]

[116]
Zhang, J.; Boska, M.; Zheng, Y.; Liu, J.; Fox, H.S.; Xiong, H. Minocycline attenuation of rat corpus callosum abnormality mediated by low-dose lipopolysaccharide-induced microglia activation. J. Neuroinflammation,  2021, 18(1), 100.
 [http://dx.doi.org/10.1186/s12974-021-02142-x] [PMID:  33902641]

[117]
Kirk, R.A.; Kesner, R.P.; Wang, L.M.; Wu, Q.; Towner, R.A.; Hoffman, J.M.; Morton, K.A. Lipopolysaccharide exposure in a rat sepsis model results in hippocampal amyloid-β plaque and phosphorylated tau deposition and corresponding behavioral deficits. Geroscience,  2019, 41(4), 467-481.
 [http://dx.doi.org/10.1007/s11357-019-00089-9] [PMID:  31473912]

[118]
Zhu, L.; Yuan, Q.; Zeng, Z.; Zhou, R.; Luo, R.; Zhang, J.; Tsang, C.K.; Bi, W. Rifampicin suppresses amyloid-β accumulation through enhancing autophagy in the hippocampus of a lipopolysaccharide-induced mouse model of cognitive decline. J. Alzheimers Dis.,  2021, 79(3), 1171-1184.
 [http://dx.doi.org/10.3233/JAD-200690] [PMID:  33386800]

[119]
Iliff, J.J.; Wang, M.; Liao, Y.; Plogg, B.A.; Peng, W.; Gundersen, G.A.; Benveniste, H.; Vates, G.E.; Deane, R.; Goldman, S.A.; Nagelhus, E.A.; Nedergaard, M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med.,  2012, 4(147), 147ra111.
 [http://dx.doi.org/10.1126/scitranslmed.3003748] [PMID:  22896675]

[120]
Cao, X.; Xu, H.; Feng, W.; Su, D.; Xiao, M. Deletion of aquaporin-4 aggravates brain pathology after blocking of the meningeal lymphatic drainage. Brain Res. Bull.,  2018, 143, 83-96.
 [http://dx.doi.org/10.1016/j.brainresbull.2018.10.007] [PMID:  30347264]

[121]
Sun, H.; Liang, R.; Yang, B.; Zhou, Y.; Liu, M.; Fang, F.; Ding, J.; Fan, Y.; Hu, G. Aquaporin-4 mediates communication between astrocyte and microglia: Implications of neuroinflammation in experimental Parkinson’s disease. Neuroscience,  2016, 317, 65-75.
 [http://dx.doi.org/10.1016/j.neuroscience.2016.01.003] [PMID:  26774050]

[122]
Lan, Y.L.; Fang, D.Y.; Zhao, J.; Ma, T.H.; Li, S. A research update on the potential roles of aquaporin 4 in neuroinflammation. Acta Neurol. Belg.,  2016, 116(2), 127-134.
 [http://dx.doi.org/10.1007/s13760-015-0520-2] [PMID:  26259614]

[123]
Radjavi, A.; Smirnov, I.; Derecki, N.; Kipnis, J. Dynamics of the meningeal CD4+ T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. Mol. Psychiatry,  2014, 19(5), 531-532.
 [http://dx.doi.org/10.1038/mp.2013.79] [PMID:  23752249]

[124]
Negi, N.; Das, B.K. CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ. Int. Rev. Immunol.,  2018, 37(1), 57-68.
 [http://dx.doi.org/10.1080/08830185.2017.1357719] [PMID:  28961037]

[125]
Kivisäkk, P.; Imitola, J.; Rasmussen, S.; Elyaman, W.; Zhu, B.; Ransohoff, R.M.; Khoury, S.J. Localizing central nervous system immune surveillance: Meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann. Neurol.,  2009, 65(4), 457-469.
 [http://dx.doi.org/10.1002/ana.21379] [PMID:  18496841]

[126]
Tanabe, K.; Wada, J.; Sato, Y. Targeting angiogenesis and lymphangiogenesis in kidney disease. Nat. Rev. Nephrol.,  2020, 16(5), 289-303.
 [http://dx.doi.org/10.1038/s41581-020-0260-2] [PMID:  32144398]

[127]
Yoshimatsu, Y.; Miyazaki, H.; Watabe, T. Roles of signaling and transcriptional networks in pathological lymphangiogenesis. Adv Drug Deliv Rev,  2016, 99(Pt B), 161-171.2016, 
 [http://dx.doi.org/10.1016/j.addr.2016.01.020] [PMID: 26850127]

[128]
Varricchi, G.; Granata, F.; Loffredo, S.; Genovese, A.; Marone, G. Angiogenesis and lymphangiogenesis in inflammatory skin disorders. J. Am. Acad. Dermatol.,  2015, 73(1), 144-153.
 [http://dx.doi.org/10.1016/j.jaad.2015.03.041] [PMID:  25922287]

[129]
Hsu, M.; Rayasam, A.; Kijak, J.A.; Choi, Y.H.; Harding, J.S.; Marcus, S.A.; Karpus, W.J.; Sandor, M.; Fabry, Z. Neuroinflammation-induced lymphangiogenesis near the cribriform plate contributes to drainage of CNS-derived antigens and immune cells. Nat. Commun.,  2019, 10(1), 229.
 [http://dx.doi.org/10.1038/s41467-018-08163-0] [PMID:  30651548]

[130]
Lawson, N.D. On the right track: Meningeal lymphatics guide angiogenesis during tissue repair in the brain. Dev. Cell,  2019, 49(5), 655-656.
 [http://dx.doi.org/10.1016/j.devcel.2019.05.029] [PMID:  31163169]

[131]
Koh, B.I.; Lee, H.J.; Kwak, P.A.; Yang, M.J.; Kim, J.H.; Kim, H.S.; Koh, G.Y.; Kim, I. VEGFR2 signaling drives meningeal vascular regeneration upon head injury. Nat. Commun.,  2020, 11(1), 3866.
 [http://dx.doi.org/10.1038/s41467-020-17545-2] [PMID:  32737287]

[132]
Bower, N.I.; Koltowska, K.; Pichol-Thievend, C.; Virshup, I.; Paterson, S.; Lagendijk, A.K.; Wang, W.; Lindsey, B.W.; Bent, S.J.; Baek, S.; Rondon-Galeano, M.; Hurley, D.G.; Mochizuki, N.; Simons, C.; Francois, M.; Wells, C.A.; Kaslin, J.; Hogan, B.M. Mural lymphatic endothelial cells regulate meningeal angiogenesis in the zebrafish. Nat. Neurosci.,  2017, 20(6), 774-783.
 [http://dx.doi.org/10.1038/nn.4558] [PMID:  28459441]

[133]
Jurisic, G.; Maby-El Hajjami, H.; Karaman, S.; Ochsenbein, A.M.; Alitalo, A.; Siddiqui, S.S.; Ochoa Pereira, C.; Petrova, T.V.; Detmar, M. An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation. Circ. Res.,  2012, 111(4), 426-436.
 [http://dx.doi.org/10.1161/CIRCRESAHA.112.269399] [PMID:  22723300]

[134]
Greenberg, S.M.; Bacskai, B.J.; Hernandez-Guillamon, M.; Pruzin, J.; Sperling, R.; van Veluw, S.J. Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways. Nat. Rev. Neurol.,  2020, 16(1), 30-42.
 [http://dx.doi.org/10.1038/s41582-019-0281-2] [PMID:  31827267]

[135]
Asby, D.; Boche, D.; Allan, S.; Love, S.; Miners, J.S. Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease. Brain,  2021, 144(6), 1869-1883.
 [http://dx.doi.org/10.1093/brain/awab094] [PMID:  33723589]

[136]
Li, Y.; Wu, P.; Bihl, J.C.; Shi, H. Underlying mechanisms and potential therapeutic molecular targets in blood-brain barrier disruption after subarachnoid hemorrhage. Curr. Neuropharmacol.,  2020, 18(12), 1168-1179.
 [http://dx.doi.org/10.2174/1570159X18666200106154203] [PMID:  31903882]

[137]
Mentis, A.F.A.; Dardiotis, E.; Chrousos, G.P. Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework. Mol. Psychiatry,  2021, 26(4), 1075-1097.
 [http://dx.doi.org/10.1038/s41380-020-0731-7] [PMID:  32355332]

[138]
Soto-Rojas, L.O.; Campa-Córdoba, B.B.; Harrington, C.R.; Salas-Casas, A.; Hernandes-Alejandro, M.; Villanueva-Fierro, I.; Bravo-Muñoz, M.; Garcés-Ramírez, L.; De La Cruz-López, F.; Ontiveros-Torres, M.Á.; Gevorkian, G.; Pacheco-Herrero, M.; Luna-Muñoz, J. Insoluble vascular amyloid deposits trigger disruption of the neurovascular unit in Alzheimer’s disease brains. Int. J. Mol. Sci.,  2021, 22(7), 3654.
 [http://dx.doi.org/10.3390/ijms22073654] [PMID:  33915754]

[139]
Szu, J.I.; Obenaus, A. Cerebrovascular phenotypes in mouse models of Alzheimer’s disease. J. Cereb. Blood Flow Metab.,  2021, 41(8), 1821-1841.
 [http://dx.doi.org/10.1177/0271678X21992462] [PMID:  33557692]

[140]
Janota, C.; Lemere, C.A.; Brito, M.A. Dissecting the contribution of vascular alterations and aging to Alzheimer’s disease. Mol. Neurobiol.,  2016, 53(6), 3793-3811.
 [http://dx.doi.org/10.1007/s12035-015-9319-7] [PMID:  26143259]

[141]
Gireud-Goss, M.; Mack, A.F.; McCullough, L.D.; Urayama, A. Cerebral amyloid angiopathy and blood-brain barrier dysfunction. Neuroscientist,  2021, 27(6), 668-684.
 [http://dx.doi.org/10.1177/1073858420954811] [PMID:  33238806]

[142]
Yamazaki, Y.; Zhao, N.; Caulfield, T.R.; Liu, C.C.; Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol.,  2019, 15(9), 501-518.
 [http://dx.doi.org/10.1038/s41582-019-0228-7] [PMID:  31367008]

[143]
Perry, V.H.; Nicoll, J.A.R.; Holmes, C. Microglia in neurodegenerative disease. Nat. Rev. Neurol.,  2010, 6(4), 193-201.
 [http://dx.doi.org/10.1038/nrneurol.2010.17] [PMID:  20234358]

[144]
Li, C.Q.; Zheng, Q.; Wang, Q.; Zeng, Q.P. Biotic/abiotic stress-driven Alzheimer’s disease. Front. Cell. Neurosci.,  2016, 10, 269.
 [http://dx.doi.org/10.3389/fncel.2016.00269] [PMID:  27932953]

[145]
Varatharaj, A.; Galea, I. The blood-brain barrier in systemic inflammation. Brain Behav. Immun.,  2017, 60, 1-12.
 [http://dx.doi.org/10.1016/j.bbi.2016.03.010] [PMID:  26995317]

[146]
Vargas-Caraveo, A.; Sayd, A.; Maus, S.R.; Caso, J.R.; Madrigal, J.L.M.; García-Bueno, B.; Leza, J.C. Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions. Sci. Rep.,  2017, 7(1), 13113.
 [http://dx.doi.org/10.1038/s41598-017-13302-6] [PMID:  29030613]

[147]
Sumbria, R.K.; Grigoryan, M.M.; Vasilevko, V.; Krasieva, T.B.; Scadeng, M.; Dvornikova, A.K.; Paganini-Hill, A.; Kim, R.; Cribbs, D.H.; Fisher, M.J. A murine model of inflammation-induced cerebral microbleeds. J. Neuroinflammation,  2016, 13(1), 218.
 [http://dx.doi.org/10.1186/s12974-016-0693-5] [PMID:  27577728]

[148]
Banks, W.A.; Gray, A.M.; Erickson, M.A.; Salameh, T.S.; Damodarasamy, M.; Sheibani, N.; Meabon, J.S.; Wing, E.E.; Morofuji, Y.; Cook, D.G.; Reed, M.J. Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J. Neuroinflammation,  2015, 12(1), 223.
 [http://dx.doi.org/10.1186/s12974-015-0434-1] [PMID:  26608623]

[149]
Mizobuchi, H.; Soma, G.I. Low-dose lipopolysaccharide as an immune regulator for homeostasis maintenance in the central nervous system through transformation to neuroprotective microglia. Neural Regen. Res.,  2021, 16(10), 1928-1934.
 [http://dx.doi.org/10.4103/1673-5374.308067] [PMID:  33642362]

[150]
Plog, B.A.; Lou, N.; Pierre, C.A.; Cove, A.; Kenney, H.M.; Hitomi, E.; Kang, H.; Iliff, J.J.; Zeppenfeld, D.M.; Nedergaard, M.; Vates, G.E. When the air hits your brain: decreased arterial pulsatility after craniectomy leading to impaired glymphatic flow. J. Neurosurg.,  2019, 1-14.
 [PMID:  31100725]

[151]
Holste, K.G.; Xia, F.; Ye, F.; Keep, R.F.; Xi, G. Mechanisms of neuroinflammation in hydrocephalus after intraventricular hemorrhage: a review. Fluids Barriers CNS,  2022, 19(1), 28.
 [http://dx.doi.org/10.1186/s12987-022-00324-0] [PMID:  35365172]

[152]
Haider, M.N.; Leddy, J.J.; Hinds, A.L.; Aronoff, N.; Rein, D.; Poulsen, D.; Willer, B.S. Intracranial pressure changes after mild traumatic brain injury: a systematic review. Brain Inj.,  2018, 32(7), 809-815.
 [http://dx.doi.org/10.1080/02699052.2018.1469045] [PMID:  29701515]

[153]
Mortimer, J.A.; Van Duijn, C.M.; Chandra, V.; Fratiglioni, L.; Graves, A.B.; Heyman, A.; Jorm, A.F.; Kokmen, E.; Kondo, K.; Rocca, W.A.; Shalat, S.L.; Soininen, H.; Hofman, A. Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of case-control studies. Int. J. Epidemiol.,  1991, 20(Suppl. 2), S28-S35.
 [http://dx.doi.org/10.1093/ije/20.Supplement_2.S28] [PMID:  1833351]

[154]
Gardner, R.C.; Burke, J.F.; Nettiksimmons, J.; Goldman, S.; Tanner, C.M.; Yaffe, K. Traumatic brain injury in later life increases risk for Parkinson disease. Ann. Neurol.,  2015, 77(6), 987-995.
 [http://dx.doi.org/10.1002/ana.24396] [PMID:  25726936]

[155]
Liu, G.; Ou, S.; Cui, H.; Li, X.; Yin, Z.; Gu, D.; Wang, Z. Head injury and amyotrophic lateral sclerosis: A meta-analysis. Neuroepidemiology,  2021, 55(1), 11-19.
 [http://dx.doi.org/10.1159/000510987] [PMID:  33621971]

[156]
Pu, T.; Zou, W.; Feng, W.; Zhang, Y.; Wang, L.; Wang, H.; Xiao, M. Persistent malfunction of glymphatic and meningeal lymphatic drainage in a mouse model of subarachnoid hemorrhage. Exp. Neurobiol.,  2019, 28(1), 104-118.
 [http://dx.doi.org/10.5607/en.2019.28.1.104] [PMID:  30853828]

[157]
Calabrese, V.; Mancuso, C.; Calvani, M.; Rizzarelli, E.; Butterfield, D.A.; Giuffrida Stella, A.M. Nitric oxide in the central nervous system: Neuroprotection versus neurotoxicity. Nat. Rev. Neurosci.,  2007, 8(10), 766-775.
 [http://dx.doi.org/10.1038/nrn2214] [PMID:  17882254]

[158]
Perluigi, M.; Di Domenico, F.; Giorgi, A.; Schininà, M.E.; Coccia, R.; Cini, C.; Bellia, F.; Cambria, M.T.; Cornelius, C.; Butterfield, D.A.; Calabrese, V. Redox proteomics in aging rat brain: Involvement of mitochondrial reduced glutathione status and mitochondrial protein oxidation in the aging process. J. Neurosci. Res.,  2010, 88(16), 3498-3507.
 [http://dx.doi.org/10.1002/jnr.22500] [PMID:  20936692]

[159]
Drake, J.; Sultana, R.; Aksenova, M.; Calabrese, V.; Butterfield, D.A. Elevation of mitochondrial glutathione by gamma-glutamylcysteine ethyl ester protects mitochondria against peroxynitrite-induced oxidative stress. J. Neurosci. Res.,  2003, 74(6), 917-927.
 [http://dx.doi.org/10.1002/jnr.10810] [PMID:  14648597]

[160]
Singla, B.; Aithabathula, R.V.; Kiran, S.; Kapil, S.; Kumar, S.; Singh, U.P. Reactive oxygen species in regulating lymphangiogenesis and lymphatic function. Cells,  2022, 11(11), 1750.
 [http://dx.doi.org/10.3390/cells11111750] [PMID:  35681445]

[161]
Calabrese, V.; Cornelius, C.; Dinkova-Kostova, A.T.; Calabrese, E.J.; Mattson, M.P. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid. Redox Signal.,  2010, 13(11), 1763-1811.
 [http://dx.doi.org/10.1089/ars.2009.3074] [PMID:  20446769]
Rights & Permissions Print Cite
Article Metrics
52
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1570159X21666221115150253	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190
Current Neuropharmacology

The Interplay between Meningeal Lymphatic Vessels and Neuroinflammation in Neurodegenerative Diseases

Abstract

Graphical Abstract

Current Neuropharmacology

The Interplay between Meningeal Lymphatic Vessels and Neuroinflammation in Neurodegenerative Diseases

Abstract

Graphical Abstract

Related Journals

Related Books
