Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?
Abstract
:1. Introduction
2. Mechanism of Disease Progression in MS
2.1. Microglia—Heterogeneity and Plasticity
2.2. The Role of Microglia in MS Progression
2.3. Biomarkers
3. Therapeutic Strategies to Stop MS Progression
3.1. Ocrelizumab—Targeting CNS-Established B Cells?
3.2. The Sphingosine-1-Phosphate Receptor System
3.3. Modulating an Activating Enzyme: Bruton’s Tyrosine Kinase
3.4. Controlling Microglia Development and Maintenance: The CSF-1R System
3.5. TREM2: A Critical Modulator of Microglia Function
3.6. CX3CR1 Expression on Microglia: A Switch towards an Inhibitory Phenotype?
3.7. The Purinergic Receptor P2X4: Regulator towards Remyelination?
4. Targeting Microglia Remains Challenging
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Lublin, F.D.; Reingold, S.C.; Cohen, J.A.; Cutter, G.R.; Sorensen, P.S.; Thompson, A.J.; Wolinsky, J.S.; Balcer, L.J.; Banwell, B.; Barkhof, F.; et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014, 83, 278–286. [Google Scholar] [CrossRef] [Green Version]
- Costello, F.; Stuve, O.; Weber, M.S.; Zamvil, S.S.; Frohman, E. Combination therapies for multiple sclerosis: Scientific rationale, clinical trials, and clinical practice. Curr. Opin. Neurol. 2007, 20, 281–285. [Google Scholar] [CrossRef]
- U.S. Food and Drug Administration News Release. FDA Approves New Drug to Treat Multiple Sclerosis. First Drug Approved for Primary Progressive MS. 2018. Available online: https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-multiple-sclerosis (accessed on 12 January 2021).
- European Medicines Agency Press Release. New Medicine for Multiple Sclerosis. 2017. Available online: https://www.ema.europa.eu/en/news/new-medicine-multiple-sclerosis (accessed on 12 January 2021).
- Rommer, P.S.; Milo, R.; Han, M.H.; Satyanarayan, S.; Sellner, J.; Hauer, L.; Illes, Z.; Warnke, C.; Laurent, S.; Weber, M.S.; et al. Immunological Aspects of Approved MS Therapeutics. Front. Immunol. 2019, 10, 1564. [Google Scholar] [CrossRef]
- Correale, J.; Gaitan, M.I.; Ysrraelit, M.C.; Fiol, M.P. Progressive multiple sclerosis: From pathogenic mechanisms to treatment. Brain 2017, 140, 527–546. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brown, J.W.L.; Coles, A.; Horakova, D.; Havrdova, E.; Izquierdo, G.; Prat, A.; Girard, M.; Duquette, P.; Trojano, M.; Lugaresi, A.; et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA 2019, 321, 175–187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sucksdorff, M.; Tuisku, J.; Matilainen, M.; Vuorimaa, A.; Smith, S.; Keitila, J.; Rokka, J.; Parkkola, R.; Nylund, M.; Rinne, J.; et al. Natalizumab treatment reduces microglial activation in the white matter of the MS brain. Neurol. Neuroimmunol. Neuroinflamm. 2019, 6, e574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nave, K.A.; Trapp, B.D. Axon-glial signaling and the glial support of axon function. Annu. Rev. Neurosci. 2008, 31, 535–561. [Google Scholar] [CrossRef] [Green Version]
- Hochmeister, S.; Grundtner, R.; Bauer, J.; Engelhardt, B.; Lyck, R.; Gordon, G.; Korosec, T.; Kutzelnigg, A.; Berger, J.J.; Bradl, M.; et al. Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J. Neuropathol. Exp. Neurol. 2006, 65, 855–865. [Google Scholar] [CrossRef] [Green Version]
- Lisak, R.P.; Benjamins, J.A.; Bealmear, B.; Nedelkoska, L.; Studzinski, D.; Retland, E.; Yao, B.; Land, S. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation in central nervous system mixed glial cell cultures. J. Neuroinflamm. 2009, 6, 4. [Google Scholar] [CrossRef] [Green Version]
- Abdelhak, A.; Weber, M.S.; Tumani, H. Primary Progressive Multiple Sclerosis: Putting Together the Puzzle. Front. Neurol. 2017, 8, 234. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lucchinetti, C.F.; Popescu, B.F.; Bunyan, R.F.; Moll, N.M.; Roemer, S.F.; Lassmann, H.; Bruck, W.; Parisi, J.E.; Scheithauer, B.W.; Giannini, C.; et al. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 2011, 365, 2188–2197. [Google Scholar] [CrossRef] [Green Version]
- Smolders, J.; Heutinck, K.M.; Fransen, N.L.; Remmerswaal, E.B.M.; Hombrink, P.; Ten Berge, I.J.M.; van Lier, R.A.W.; Huitinga, I.; Hamann, J. Tissue-resident memory T cells populate the human brain. Nat. Commun. 2018, 9, 4593. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Konjevic Sabolek, M.; Held, K.; Beltran, E.; Niedl, A.G.; Meinl, E.; Hohlfeld, R.; Lassmann, H.; Dornmair, K. Communication of CD8(+) T cells with mononuclear phagocytes in multiple sclerosis. Ann. Clin. Transl. Neurol. 2019, 6, 1151–1164. [Google Scholar] [CrossRef] [Green Version]
- Machado-Santos, J.; Saji, E.; Troscher, A.R.; Paunovic, M.; Liblau, R.; Gabriely, G.; Bien, C.G.; Bauer, J.; Lassmann, H. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 2018, 141, 2066–2082. [Google Scholar] [CrossRef] [PubMed]
- Rommer, P.S.; Weber, M.S.; Illes, Z.; Zettl, U.K. Editorial: Multiple Sclerosis—From Bench to Bedside: Currents Insights into Pathophysiological Concepts and Their Potential Impact on Patients. Front. Immunol. 2020, 11, 137. [Google Scholar] [CrossRef] [Green Version]
- Magliozzi, R.; Howell, O.; Vora, A.; Serafini, B.; Nicholas, R.; Puopolo, M.; Reynolds, R.; Aloisi, F. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007, 130, 1089–1104. [Google Scholar] [CrossRef] [PubMed]
- Krumbholz, M.; Theil, D.; Derfuss, T.; Rosenwald, A.; Schrader, F.; Monoranu, C.M.; Kalled, S.L.; Hess, D.M.; Serafini, B.; Aloisi, F.; et al. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J. Exp. Med. 2005, 201, 195–200. [Google Scholar] [CrossRef]
- Lassmann, H.; van Horssen, J. Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim. Biophys. Acta 2016, 1862, 506–510. [Google Scholar] [CrossRef] [PubMed]
- Perry, V.H.; Gordon, S. Macrophages and microglia in the nervous system. Trends Neurosci. 1988, 11, 273–277. [Google Scholar] [CrossRef]
- Kreutzberg, G.W. Microglia: A sensor for pathological events in the CNS. Trends Neurosci. 1996, 19, 312–318. [Google Scholar] [CrossRef]
- Ginhoux, F.; Lim, S.; Hoeffel, G.; Low, D.; Huber, T. Origin and differentiation of microglia. Front. Cell Neurosci. 2013, 7, 45. [Google Scholar] [CrossRef] [Green Version]
- Kettenmann, H.; Hanisch, U.K.; Noda, M.; Verkhratsky, A. Physiology of microglia. Physiol. Rev. 2011, 91, 461–553. [Google Scholar] [CrossRef]
- Martinez, F.O.; Sica, A.; Mantovani, A.; Locati, M. Macrophage activation and polarization. Front. Biosci. 2008, 13, 453–461. [Google Scholar] [CrossRef] [Green Version]
- Chhor, V.; Le Charpentier, T.; Lebon, S.; Ore, M.V.; Celador, I.L.; Josserand, J.; Degos, V.; Jacotot, E.; Hagberg, H.; Savman, K.; et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav. Immun. 2013, 32, 70–85. [Google Scholar] [CrossRef] [PubMed]
- Aguzzi, A.; Barres, B.A.; Bennett, M.L. Microglia: Scapegoat, saboteur, or something else? Science 2013, 339, 156–161. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schetters, S.T.T.; Gomez-Nicola, D.; Garcia-Vallejo, J.J.; Van Kooyk, Y. Neuroinflammation: Microglia and T Cells Get Ready to Tango. Front. Immunol. 2017, 8, 1905. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ding, A.H.; Nathan, C.F.; Stuehr, D.J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J. Immunol. 1988, 141, 2407–2412. [Google Scholar]
- Colton, C.A.; Gilbert, D.L. Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett. 1987, 223, 284–288. [Google Scholar] [CrossRef] [Green Version]
- Frischer, J.M.; Bramow, S.; Dal-Bianco, A.; Lucchinetti, C.F.; Rauschka, H.; Schmidbauer, M.; Laursen, H.; Sorensen, P.S.; Lassmann, H. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009, 132, 1175–1189. [Google Scholar] [CrossRef] [Green Version]
- Lucchinetti, C.; Bruck, W.; Parisi, J.; Scheithauer, B.; Rodriguez, M.; Lassmann, H. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann. Neurol. 2000, 47, 707–717. [Google Scholar] [CrossRef]
- Kuhlmann, T.; Ludwin, S.; Prat, A.; Antel, J.; Bruck, W.; Lassmann, H. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017, 133, 13–24. [Google Scholar] [CrossRef] [PubMed]
- Zrzavy, T.; Hametner, S.; Wimmer, I.; Butovsky, O.; Weiner, H.L.; Lassmann, H. Loss of ’homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 2017, 140, 1900–1913. [Google Scholar] [CrossRef]
- De Groot, C.J.; Bergers, E.; Kamphorst, W.; Ravid, R.; Polman, C.H.; Barkhof, F.; van der Valk, P. Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: Increased yield of active demyelinating and (p)reactive lesions. Brain 2001, 124, 1635–1645. [Google Scholar] [CrossRef] [Green Version]
- Van der Poel, M.; Ulas, T.; Mizee, M.R.; Hsiao, C.C.; Miedema, S.S.M.; Adelia; Schuurman, K. G.; Helder, B.; Tas, S.W.; Schultze, J.L.; et al. Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes. Nat. Commun. 2019, 10, 1139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Giannetti, P.; Politis, M.; Su, P.; Turkheimer, F.; Malik, O.; Keihaninejad, S.; Wu, K.; Reynolds, R.; Nicholas, R.; Piccini, P. Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: An in vivo [(11)C](R)-PK11195-PET pilot study. Neurobiol. Dis. 2014, 65, 203–210. [Google Scholar] [CrossRef]
- Bottcher, C.; van der Poel, M.; Fernandez-Zapata, C.; Schlickeiser, S.; Leman, J.K.H.; Hsiao, C.C.; Mizee, M.R.; Adelia; Vincenten, M. C.J.; Kunkel, D.; et al. Single-cell mass cytometry reveals complex myeloid cell composition in active lesions of progressive multiple sclerosis. Acta Neuropathol. Commun. 2020, 8, 136. [Google Scholar] [CrossRef]
- O’Loughlin, E.; Madore, C.; Lassmann, H.; Butovsky, O. Microglial Phenotypes and Functions in Multiple Sclerosis. Cold Spring Harb. Perspect. Med. 2018, 8. [Google Scholar] [CrossRef] [PubMed]
- Liddelow, S.A.; Guttenplan, K.A.; Clarke, L.E.; Bennett, F.C.; Bohlen, C.J.; Schirmer, L.; Bennett, M.L.; Munch, A.E.; Chung, W.S.; Peterson, T.C.; et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017, 541, 481–487. [Google Scholar] [CrossRef]
- Rothhammer, V.; Borucki, D.M.; Tjon, E.C.; Takenaka, M.C.; Chao, C.C.; Ardura-Fabregat, A.; de Lima, K.A.; Gutierrez-Vazquez, C.; Hewson, P.; Staszewski, O.; et al. Microglial control of astrocytes in response to microbial metabolites. Nature 2018, 557, 724–728. [Google Scholar] [CrossRef]
- Fischer, M.T.; Sharma, R.; Lim, J.L.; Haider, L.; Frischer, J.M.; Drexhage, J.; Mahad, D.; Bradl, M.; van Horssen, J.; Lassmann, H. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 2012, 135, 886–899. [Google Scholar] [CrossRef] [Green Version]
- Campbell, G.R.; Ziabreva, I.; Reeve, A.K.; Krishnan, K.J.; Reynolds, R.; Howell, O.; Lassmann, H.; Turnbull, D.M.; Mahad, D.J. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann. Neurol. 2011, 69, 481–492. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mahad, D.J.; Ziabreva, I.; Campbell, G.; Lax, N.; White, K.; Hanson, P.S.; Lassmann, H.; Turnbull, D.M. Mitochondrial changes within axons in multiple sclerosis. Brain 2009, 132, 1161–1174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hametner, S.; Wimmer, I.; Haider, L.; Pfeifenbring, S.; Bruck, W.; Lassmann, H. Iron and neurodegeneration in the multiple sclerosis brain. Ann. Neurol. 2013, 74, 848–861. [Google Scholar] [CrossRef] [PubMed]
- Karamita, M.; Barnum, C.; Mobius, W.; Tansey, M.G.; Szymkowski, D.E.; Lassmann, H.; Probert, L. Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia. JCI Insight 2017, 2. [Google Scholar] [CrossRef] [Green Version]
- Lampron, A.; Larochelle, A.; Laflamme, N.; Prefontaine, P.; Plante, M.M.; Sanchez, M.G.; Yong, V.W.; Stys, P.K.; Tremblay, M.E.; Rivest, S. Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J. Exp. Med. 2015, 212, 481–495. [Google Scholar] [CrossRef] [Green Version]
- Yamasaki, R.; Lu, H.; Butovsky, O.; Ohno, N.; Rietsch, A.M.; Cialic, R.; Wu, P.M.; Doykan, C.E.; Lin, J.; Cotleur, A.C.; et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 2014, 211, 1533–1549. [Google Scholar] [CrossRef] [Green Version]
- Poliani, P.L.; Wang, Y.; Fontana, E.; Robinette, M.L.; Yamanishi, Y.; Gilfillan, S.; Colonna, M. TREM2 sustains microglial expansion during aging and response to demyelination. J. Clin. Investig. 2015, 125, 2161–2170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Boyd, A.; Zhang, H.; Williams, A. Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathol. 2013, 125, 841–859. [Google Scholar] [CrossRef] [Green Version]
- Franklin, R.J.; Goldman, S.A. Glia Disease and Repair-Remyelination. Cold Spring Harb. Perspect. Biol. 2015, 7, a020594. [Google Scholar] [CrossRef]
- Miron, V.E.; Boyd, A.; Zhao, J.W.; Yuen, T.J.; Ruckh, J.M.; Shadrach, J.L.; van Wijngaarden, P.; Wagers, A.J.; Williams, A.; Franklin, R.J.M.; et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 2013, 16, 1211–1218. [Google Scholar] [CrossRef] [Green Version]
- Starossom, S.C.; Mascanfroni, I.D.; Imitola, J.; Cao, L.; Raddassi, K.; Hernandez, S.F.; Bassil, R.; Croci, D.O.; Cerliani, J.P.; Delacour, D.; et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity 2012, 37, 249–263. [Google Scholar] [CrossRef] [Green Version]
- Yu, Z.; Sun, D.; Feng, J.; Tan, W.; Fang, X.; Zhao, M.; Zhao, X.; Pu, Y.; Huang, A.; Xiang, Z.; et al. MSX3 Switches Microglia Polarization and Protects from Inflammation-Induced Demyelination. J. Neurosci. 2015, 35, 6350–6365. [Google Scholar] [CrossRef] [Green Version]
- Lloyd, A.F.; Davies, C.L.; Holloway, R.K.; Labrak, Y.; Ireland, G.; Carradori, D.; Dillenburg, A.; Borger, E.; Soong, D.; Richardson, J.C.; et al. Central nervous system regeneration is driven by microglia necroptosis and repopulation. Nat. Neurosci. 2019, 22, 1046–1052. [Google Scholar] [CrossRef]
- Ofengeim, D.; Ito, Y.; Najafov, A.; Zhang, Y.; Shan, B.; DeWitt, J.P.; Ye, J.; Zhang, X.; Chang, A.; Vakifahmetoglu-Norberg, H.; et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 2015, 10, 1836–1849. [Google Scholar] [CrossRef] [Green Version]
- Djedovic, N.; Stanisavljevic, S.; Jevtic, B.; Momcilovic, M.; Lavrnja, I.; Miljkovic, D. Anti-encephalitogenic effects of ethyl pyruvate are reflected in the central nervous system and the gut. Biomed. Pharmacother. 2017, 96, 78–85. [Google Scholar] [CrossRef] [PubMed]
- Airas, L.; Nylund, M.; Rissanen, E. Evaluation of Microglial Activation in Multiple Sclerosis Patients Using Positron Emission Tomography. Front. Neurol. 2018, 9, 181. [Google Scholar] [CrossRef] [Green Version]
- Herranz, E.; Gianni, C.; Louapre, C.; Treaba, C.A.; Govindarajan, S.T.; Ouellette, R.; Loggia, M.L.; Sloane, J.A.; Madigan, N.; Izquierdo-Garcia, D.; et al. Neuroinflammatory component of gray matter pathology in multiple sclerosis. Ann. Neurol. 2016, 80, 776–790. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rissanen, E.; Tuisku, J.; Rokka, J.; Paavilainen, T.; Parkkola, R.; Rinne, J.O.; Airas, L. In Vivo Detection of Diffuse Inflammation in Secondary Progressive Multiple Sclerosis Using PET Imaging and the Radioligand (1)(1)C-PK11195. J. Nucl. Med. 2014, 55, 939–944. [Google Scholar] [CrossRef] [Green Version]
- Sucksdorff, M.; Matilainen, M.; Tuisku, J.; Polvinen, E.; Vuorimaa, A.; Rokka, J.; Nylund, M.; Rissanen, E.; Airas, L. Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis. Brain 2020, 143, 3318–3330. [Google Scholar] [CrossRef]
- Piccio, L.; Buonsanti, C.; Cella, M.; Tassi, I.; Schmidt, R.E.; Fenoglio, C.; Rinker, J., II; Naismith, R.T.; Panina-Bordignon, P.; Passini, N.; et al. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain 2008, 131, 3081–3091. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ohrfelt, A.; Axelsson, M.; Malmestrom, C.; Novakova, L.; Heslegrave, A.; Blennow, K.; Lycke, J.; Zetterberg, H. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Mult. Scler. 2016, 22, 1587–1595. [Google Scholar] [CrossRef] [PubMed]
- Budnik, V.; Ruiz-Canada, C.; Wendler, F. Extracellular vesicles round off communication in the nervous system. Nat. Rev. Neurosci. 2016, 17, 160–172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verderio, C.; Muzio, L.; Turola, E.; Bergami, A.; Novellino, L.; Ruffini, F.; Riganti, L.; Corradini, I.; Francolini, M.; Garzetti, L.; et al. Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann. Neurol. 2012, 72, 610–624. [Google Scholar] [CrossRef] [Green Version]
- Montalban, X.; Hauser, S.L.; Kappos, L.; Arnold, D.L.; Bar-Or, A.; Comi, G.; de Seze, J.; Giovannoni, G.; Hartung, H.P.; Hemmer, B.; et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N. Engl. J. Med. 2017, 376, 209–220. [Google Scholar] [CrossRef] [PubMed]
- Hawker, K.; O’Connor, P.; Freedman, M.S.; Calabresi, P.A.; Antel, J.; Simon, J.; Hauser, S.; Waubant, E.; Vollmer, T.; Panitch, H.; et al. Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann. Neurol. 2009, 66, 460–471. [Google Scholar] [CrossRef]
- Matloubian, M.; Lo, C.G.; Cinamon, G.; Lesneski, M.J.; Xu, Y.; Brinkmann, V.; Allende, M.L.; Proia, R.L.; Cyster, J.G. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004, 427, 355–360. [Google Scholar] [CrossRef]
- Kappos, L.; Bar-Or, A.; Cree, B.A.C.; Fox, R.J.; Giovannoni, G.; Gold, R.; Vermersch, P.; Arnold, D.L.; Arnould, S.; Scherz, T.; et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double-blind, randomised, phase 3 study. Lancet 2018, 391, 1263–1273. [Google Scholar] [CrossRef]
- Lublin, F.; Miller, D.H.; Freedman, M.S.; Cree, B.A.C.; Wolinsky, J.S.; Weiner, H.; Lubetzki, C.; Hartung, H.P.; Montalban, X.; Uitdehaag, B.M.J.; et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): A phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016, 387, 1075–1084. [Google Scholar] [CrossRef]
- Kipp, M. Does Siponimod Exert Direct Effects in the Central Nervous System? Cells 2020, 9, 1771. [Google Scholar] [CrossRef]
- Foster, C.A.; Howard, L.M.; Schweitzer, A.; Persohn, E.; Hiestand, P.C.; Balatoni, B.; Reuschel, R.; Beerli, C.; Schwartz, M.; Billich, A. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: Consequences for mode of action in multiple sclerosis. J. Pharmacol. Exp. Ther. 2007, 323, 469–475. [Google Scholar] [CrossRef] [Green Version]
- Husseini, L.; Geladaris, A.; Steinleitner, M.; Grondey, K.; Koch, J.; Häusler, D.; Weber, M. Siponimod treatment leads to a dose-dependent reduction of EAE severity associated with downregulation of microglial activity. MSVirtual 2020, 26, 308–309. [Google Scholar]
- O’Sullivan, C.; Schubart, A.; Mir, A.K.; Dev, K.K. The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures. J. Neuroinflamm. 2016, 13, 31. [Google Scholar] [CrossRef] [Green Version]
- Gentile, A.; Musella, A.; Bullitta, S.; Fresegna, D.; De Vito, F.; Fantozzi, R.; Piras, E.; Gargano, F.; Borsellino, G.; Battistini, L.; et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J. Neuroinflamm. 2016, 13, 207. [Google Scholar] [CrossRef] [Green Version]
- Colombo, E.; Bassani, C.; De Angelis, A.; Ruffini, F.; Ottoboni, L.; Comi, G.; Martino, G.; Farina, C. Siponimod (BAF312) Activates Nrf2 While Hampering NFkappaB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration. Front. Immunol. 2020, 11, 635. [Google Scholar] [CrossRef] [PubMed]
- Draheim, T.; Liessem, A.; Scheld, M.; Wilms, F.; Weissflog, M.; Denecke, B.; Kensler, T.W.; Zendedel, A.; Beyer, C.; Kipp, M.; et al. Activation of the astrocytic Nrf2/ARE system ameliorates the formation of demyelinating lesions in a multiple sclerosis animal model. Glia 2016, 64, 2219–2230. [Google Scholar] [CrossRef]
- Mannioui, A.; Vauzanges, Q.; Fini, J.B.; Henriet, E.; Sekizar, S.; Azoyan, L.; Thomas, J.L.; Pasquier, D.D.; Giovannangeli, C.; Demeneix, B.; et al. The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination. Mult. Scler. 2018, 24, 1421–1432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hendriks, R.W.; Yuvaraj, S.; Kil, L.P. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat. Rev. Cancer 2014, 14, 219–232. [Google Scholar] [CrossRef]
- Lopez-Herrera, G.; Vargas-Hernandez, A.; Gonzalez-Serrano, M.E.; Berron-Ruiz, L.; Rodriguez-Alba, J.C.; Espinosa-Rosales, F.; Santos-Argumedo, L. Bruton’s tyrosine kinase—An integral protein of B cell development that also has an essential role in the innate immune system. J. Leukoc. Biol. 2014, 95, 243–250. [Google Scholar] [CrossRef] [PubMed]
- Montalban, X.; Arnold, D.L.; Weber, M.S.; Staikov, I.; Piasecka-Stryczynska, K.; Willmer, J.; Martin, E.C.; Dangond, F.; Syed, S.; Wolinsky, J.S.; et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N. Engl. J. Med. 2019, 380, 2406–2417. [Google Scholar] [CrossRef]
- Gheen, M.; Hauser, S.; Bar-Or, A.; Francis, G.; Giovannoni, G.; Kappos, L.; Nicholas, J.; Oh, J.; Sormani, M.P.; Stoll, S.; et al. Examination of fenebrutinib, a highly selective BTKi, on disease progression of multiple sclerosis. MSVirtual 2020, 26, 220. [Google Scholar]
- Humphries, L.A.; Dangelmaier, C.; Sommer, K.; Kipp, K.; Kato, R.M.; Griffith, N.; Bakman, I.; Turk, C.W.; Daniel, J.L.; Rawlings, D.J. Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker. J. Biol. Chem. 2004, 279, 37651–37661. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shillitoe, B.; Gennery, A. X-Linked Agammaglobulinaemia: Outcomes in the modern era. Clin Immunol. 2017, 183, 54–62. [Google Scholar] [CrossRef]
- Pal Singh, S.; Dammeijer, F.; Hendriks, R.W. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol. Cancer 2018, 17, 57. [Google Scholar] [CrossRef]
- Martin, E.; Aigrot, M.S.; Grenningloh, R.; Stankoff, B.; Lubetzki, C.; Boschert, U.; Zalc, B. Bruton’s Tyrosine Kinase Inhibition Promotes Myelin Repair. Brain Plasticity 2020, 5, 123–133. [Google Scholar] [CrossRef]
- Keaney, J.; Gasser, J.; Gillet, G.; Scholz, D.; Kadiu, I. Inhibition of Bruton’s Tyrosine Kinase Modulates Microglial Phagocytosis: Therapeutic Implications for Alzheimer’s Disease. J. Neuroimmune Pharmacol. 2019, 14, 448–461. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Glendenning, L.; Gruber, R.; Dufault, M.; Chretien, N.; Proto, J.; Zhang, M.; Lamorte, M.; Havari, E.; Turner, T.; Chomyk, A.; et al. Decoding Bruton’s tyrosine kinase signalling in neuroinflammation. MSVirtual 2020, 26, 270. [Google Scholar]
- Nam, H.Y.; Nam, J.H.; Yoon, G.; Lee, J.Y.; Nam, Y.; Kang, H.J.; Cho, H.J.; Kim, J.; Hoe, H.S. Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice. J. Neuroinflamm. 2018, 15, 271. [Google Scholar] [CrossRef] [Green Version]
- Menzfeld, C.; John, M.; van Rossum, D.; Regen, T.; Scheffel, J.; Janova, H.; Gotz, A.; Ribes, S.; Nau, R.; Borisch, A.; et al. Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. Glia 2015, 63, 1083–1099. [Google Scholar] [CrossRef] [Green Version]
- Shideman, C.R.; Hu, S.; Peterson, P.K.; Thayer, S.A. CCL5 evokes calcium signals in microglia through a kinase-, phosphoinositide-, and nucleotide-dependent mechanism. J. Neurosci. Res. 2006, 83, 1471–1484. [Google Scholar] [CrossRef]
- Lin, H.; Lee, E.; Hestir, K.; Leo, C.; Huang, M.; Bosch, E.; Halenbeck, R.; Wu, G.; Zhou, A.; Behrens, D.; et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 2008, 320, 807–811. [Google Scholar] [CrossRef] [Green Version]
- Stanley, E.R.; Heard, P.M. Factors regulating macrophage production and growth. Purification and some properties of the colony stimulating factor from medium conditioned by mouse L cells. J. Biol. Chem. 1977, 252, 4305–4312. [Google Scholar] [CrossRef]
- Stanley, E.R.; Chitu, V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb. Perspect. Biol. 2014, 6. [Google Scholar] [CrossRef] [Green Version]
- Elmore, M.R.; Najafi, A.R.; Koike, M.A.; Dagher, N.N.; Spangenberg, E.E.; Rice, R.A.; Kitazawa, M.; Matusow, B.; Nguyen, H.; West, B.L.; et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 2014, 82, 380–397. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hawley, C.A.; Rojo, R.; Raper, A.; Sauter, K.A.; Lisowski, Z.M.; Grabert, K.; Bain, C.C.; Davis, G.M.; Louwe, P.A.; Ostrowski, M.C.; et al. Csf1r-mApple Transgene Expression and Ligand Binding In Vivo Reveal Dynamics of CSF1R Expression within the Mononuclear Phagocyte System. J. Immunol. 2018, 200, 2209–2223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chitu, V.; Gokhan, S.; Nandi, S.; Mehler, M.F.; Stanley, E.R. Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System. Trends Neurosci. 2016, 39, 378–393. [Google Scholar] [CrossRef] [Green Version]
- Konno, T.; Yoshida, K.; Mizuno, T.; Kawarai, T.; Tada, M.; Nozaki, H.; Ikeda, S.I.; Nishizawa, M.; Onodera, O.; Wszolek, Z.K.; et al. Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation. Eur. J. Neurol. 2017, 24, 37–45. [Google Scholar] [CrossRef]
- Erblich, B.; Zhu, L.; Etgen, A.M.; Dobrenis, K.; Pollard, J.W. Absence of colony stimulation factor-1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS ONE 2011, 6, e26317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hagan, N.; Kane, J.L.; Grover, D.; Woodworth, L.; Madore, C.; Saleh, J.; Sancho, J.; Liu, J.; Li, Y.; Proto, J.; et al. CSF1R signaling is a regulator of pathogenesis in progressive MS. Cell Death Dis. 2020, 11, 904. [Google Scholar] [CrossRef]
- Nissen, J.C.; Thompson, K.K.; West, B.L.; Tsirka, S.E. Csf1R inhibition attenuates experimental autoimmune encephalomyelitis and promotes recovery. Exp. Neurol. 2018, 307, 24–36. [Google Scholar] [CrossRef] [PubMed]
- Lei, F.; Cui, N.; Zhou, C.; Chodosh, J.; Vavvas, D.G.; Paschalis, E.I. CSF1R inhibition by a small-molecule inhibitor is not microglia specific; affecting hematopoiesis and the function of macrophages. Proc. Natl. Acad. Sci. USA 2020, 117, 23336–23338. [Google Scholar] [CrossRef]
- Tahmasebi, F.; Pasbakhsh, P.; Mortezaee, K.; Madadi, S.; Barati, S.; Kashani, I.R. Effect of the CSF1R inhibitor PLX3397 on remyelination of corpus callosum in a cuprizone-induced demyelination mouse model. J. Cell Biochem. 2019, 120, 10576–10586. [Google Scholar] [CrossRef] [PubMed]
- Beckmann, N.; Giorgetti, E.; Neuhaus, A.; Zurbruegg, S.; Accart, N.; Smith, P.; Perdoux, J.; Perrot, L.; Nash, M.; Desrayaud, S.; et al. Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945. Acta Neuropathol. Commun. 2018, 6, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Luo, J.; Elwood, F.; Britschgi, M.; Villeda, S.; Zhang, H.; Ding, Z.; Zhu, L.; Alabsi, H.; Getachew, R.; Narasimhan, R.; et al. Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival. J. Exp. Med. 2013, 210, 157–172. [Google Scholar] [CrossRef] [Green Version]
- Ulland, T.K.; Colonna, M. TREM2—A key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 2018, 14, 667–675. [Google Scholar] [CrossRef] [PubMed]
- Paloneva, J.; Manninen, T.; Christman, G.; Hovanes, K.; Mandelin, J.; Adolfsson, R.; Bianchin, M.; Bird, T.; Miranda, R.; Salmaggi, A.; et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 2002, 71, 656–662. [Google Scholar] [CrossRef] [Green Version]
- Jonsson, T.; Stefansson, H.; Steinberg, S.; Jonsdottir, I.; Jonsson, P.V.; Snaedal, J.; Bjornsson, S.; Huttenlocher, J.; Levey, A.I.; Lah, J.J.; et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 2013, 368, 107–116. [Google Scholar] [CrossRef] [Green Version]
- Cuyvers, E.; Bettens, K.; Philtjens, S.; Van Langenhove, T.; Gijselinck, I.; van der Zee, J.; Engelborghs, S.; Vandenbulcke, M.; Van Dongen, J.; Geerts, N.; et al. Investigating the role of rare heterozygous TREM2 variants in Alzheimer’s disease and frontotemporal dementia. Neurobiol. Aging 2014, 35, 726.e11–726.e19. [Google Scholar] [CrossRef]
- Mittelbronn, M.; Dietz, K.; Schluesener, H.J.; Meyermann, R. Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol. 2001, 101, 249–255. [Google Scholar] [CrossRef] [PubMed]
- Forabosco, P.; Ramasamy, A.; Trabzuni, D.; Walker, R.; Smith, C.; Bras, J.; Levine, A.P.; Hardy, J.; Pocock, J.M.; Guerreiro, R.; et al. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol. Aging 2013, 34, 2699–2714. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wunderlich, P.; Glebov, K.; Kemmerling, N.; Tien, N.T.; Neumann, H.; Walter, J. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J. Biol. Chem. 2013, 288, 33027–33036. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Takahashi, K.; Rochford, C.D.; Neumann, H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 2005, 201, 647–657. [Google Scholar] [CrossRef] [Green Version]
- Takahashi, K.; Prinz, M.; Stagi, M.; Chechneva, O.; Neumann, H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 2007, 4, e124. [Google Scholar] [CrossRef] [Green Version]
- Cignarella, F.; Filipello, F.; Bollman, B.; Cantoni, C.; Locca, A.; Mikesell, R.; Manis, M.; Ibrahim, A.; Deng, L.; Benitez, B.A.; et al. TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis. Acta Neuropathol. 2020, 140, 513–534. [Google Scholar] [CrossRef] [PubMed]
- Bouchon, A.; Hernandez-Munain, C.; Cella, M.; Colonna, M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J. Exp. Med. 2001, 194, 1111–1122. [Google Scholar] [CrossRef] [Green Version]
- Kobayashi, M.; Konishi, H.; Sayo, A.; Takai, T.; Kiyama, H. TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain. J. Neurosci. 2016, 36, 11138–11150. [Google Scholar] [CrossRef] [PubMed]
- Harrison, J.K.; Jiang, Y.; Chen, S.; Xia, Y.; Maciejewski, D.; McNamara, R.K.; Streit, W.J.; Salafranca, M.N.; Adhikari, S.; Thompson, D.A.; et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. USA 1998, 95, 10896–10901. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lucas, A.D.; Chadwick, N.; Warren, B.F.; Jewell, D.P.; Gordon, S.; Powrie, F.; Greaves, D.R. The transmembrane form of the CX3CL1 chemokine fractalkine is expressed predominantly by epithelial cells in vivo. Am. J. Pathol 2001, 158, 855–866. [Google Scholar] [CrossRef] [Green Version]
- Limatola, C.; Ransohoff, R.M. Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front. Cell Neurosci. 2014, 8, 229. [Google Scholar] [CrossRef]
- Zujovic, V.; Benavides, J.; Vige, X.; Carter, C.; Taupin, V. Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia 2000, 29, 305–315. [Google Scholar] [CrossRef]
- Mizuno, T.; Kawanokuchi, J.; Numata, K.; Suzumura, A. Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res. 2003, 979, 65–70. [Google Scholar] [CrossRef]
- Murai, N.; Mitalipova, M.; Jaenisch, R. Functional analysis of CX3CR1 in human induced pluripotent stem (iPS) cell-derived microglia-like cells. Eur. J. Neurosci. 2020, 52, 3667–3678. [Google Scholar] [CrossRef]
- Lee, S.; Varvel, N.H.; Konerth, M.E.; Xu, G.; Cardona, A.E.; Ransohoff, R.M.; Lamb, B.T. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am. J. Pathol. 2010, 177, 2549–2562. [Google Scholar] [CrossRef] [PubMed]
- Liu, Z.; Condello, C.; Schain, A.; Harb, R.; Grutzendler, J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J. Neurosci. 2010, 30, 17091–17101. [Google Scholar] [CrossRef] [Green Version]
- Sunnemark, D.; Eltayeb, S.; Nilsson, M.; Wallstrom, E.; Lassmann, H.; Olsson, T.; Berg, A.L.; Ericsson-Dahlstrand, A. CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: Kinetics and cellular origin. J. Neuroinflamm. 2005, 2, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lauro, C.; Cipriani, R.; Catalano, M.; Trettel, F.; Chece, G.; Brusadin, V.; Antonilli, L.; van Rooijen, N.; Eusebi, F.; Fredholm, B.B.; et al. Adenosine A1 receptors and microglial cells mediate CX3CL1-induced protection of hippocampal neurons against Glu-induced death. Neuropsychopharmacology 2010, 35, 1550–1559. [Google Scholar] [CrossRef] [Green Version]
- Cipriani, R.; Villa, P.; Chece, G.; Lauro, C.; Paladini, A.; Micotti, E.; Perego, C.; De Simoni, M.G.; Fredholm, B.B.; Eusebi, F.; et al. CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J. Neurosci. 2011, 31, 16327–16335. [Google Scholar] [CrossRef] [Green Version]
- Catalano, M.; Lauro, C.; Cipriani, R.; Chece, G.; Ponzetta, A.; Di Angelantonio, S.; Ragozzino, D.; Limatola, C. CX3CL1 protects neurons against excitotoxicity enhancing GLT-1 activity on astrocytes. J. Neuroimmunol. 2013, 263, 75–82. [Google Scholar] [CrossRef]
- Garcia, J.A.; Pino, P.A.; Mizutani, M.; Cardona, S.M.; Charo, I.F.; Ransohoff, R.M.; Forsthuber, T.G.; Cardona, A.E. Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation. J. Immunol. 2013, 191, 1063–1072. [Google Scholar] [CrossRef] [Green Version]
- Mecca, C.; Giambanco, I.; Donato, R.; Arcuri, C. Microglia and Aging: The Role of the TREM2-DAP12 and CX3CL1-CX3CR1 Axes. Int. J. Mol. Sci. 2018, 19, 318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Imai, T.; Hieshima, K.; Haskell, C.; Baba, M.; Nagira, M.; Nishimura, M.; Kakizaki, M.; Takagi, S.; Nomiyama, H.; Schall, T.J.; et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 1997, 91, 521–530. [Google Scholar] [CrossRef] [Green Version]
- Infante-Duarte, C.; Weber, A.; Kratzschmar, J.; Prozorovski, T.; Pikol, S.; Hamann, I.; Bellmann-Strobl, J.; Aktas, O.; Dorr, J.; Wuerfel, J.; et al. Frequency of blood CX3CR1-positive natural killer cells correlates with disease activity in multiple sclerosis patients. FASEB J. 2005, 19, 1902–1904. [Google Scholar] [CrossRef] [PubMed]
- Ridderstad Wollberg, A.; Ericsson-Dahlstrand, A.; Jureus, A.; Ekerot, P.; Simon, S.; Nilsson, M.; Wiklund, S.J.; Berg, A.L.; Ferm, M.; Sunnemark, D.; et al. Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis. Proc. Natl. Acad. Sci. USA 2014, 111, 5409–5414. [Google Scholar] [CrossRef] [Green Version]
- Tsuda, M.; Shigemoto-Mogami, Y.; Koizumi, S.; Mizokoshi, A.; Kohsaka, S.; Salter, M.W.; Inoue, K. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003, 424, 778–783. [Google Scholar] [CrossRef]
- Agresti, C.; Meomartini, M.E.; Amadio, S.; Ambrosini, E.; Serafini, B.; Franchini, L.; Volonte, C.; Aloisi, F.; Visentin, S. Metabotropic P2 receptor activation regulates oligodendrocyte progenitor migration and development. Glia 2005, 50, 132–144. [Google Scholar] [CrossRef] [PubMed]
- Khoja, S.; Huynh, N.; Asatryan, L.; Jakowec, M.W.; Davies, D.L. Reduced expression of purinergic P2X4 receptors increases voluntary ethanol intake in C57BL/6J mice. Alcohol 2018, 68, 63–70. [Google Scholar] [CrossRef]
- Wyatt, L.R.; Godar, S.C.; Khoja, S.; Jakowec, M.W.; Alkana, R.L.; Bortolato, M.; Davies, D.L. Sociocommunicative and sensorimotor impairments in male P2X4-deficient mice. Neuropsychopharmacology 2013, 38, 1993–2002. [Google Scholar] [CrossRef] [Green Version]
- Vazquez-Villoldo, N.; Domercq, M.; Martin, A.; Llop, J.; Gomez-Vallejo, V.; Matute, C. P2X4 receptors control the fate and survival of activated microglia. Glia 2014, 62, 171–184. [Google Scholar] [CrossRef]
- Masuda, T.; Iwamoto, S.; Yoshinaga, R.; Tozaki-Saitoh, H.; Nishiyama, A.; Mak, T.W.; Tamura, T.; Tsuda, M.; Inoue, K. Transcription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain. Nat. Commun. 2014, 5, 3771. [Google Scholar] [CrossRef] [Green Version]
- Krausgruber, T.; Blazek, K.; Smallie, T.; Alzabin, S.; Lockstone, H.; Sahgal, N.; Hussell, T.; Feldmann, M.; Udalova, I.A. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol. 2011, 12, 231–238. [Google Scholar] [CrossRef] [PubMed]
- Tolwani, R.J.; Cosgaya, J.M.; Varma, S.; Jacob, R.; Kuo, L.E.; Shooter, E.M. BDNF overexpression produces a long-term increase in myelin formation in the peripheral nervous system. J. Neurosci. Res. 2004, 77, 662–669. [Google Scholar] [CrossRef]
- Su, W.F.; Wu, F.; Jin, Z.H.; Gu, Y.; Chen, Y.T.; Fei, Y.; Chen, H.; Wang, Y.X.; Xing, L.Y.; Zhao, Y.Y.; et al. Overexpression of P2X4 receptor in Schwann cells promotes motor and sensory functional recovery and remyelination via BDNF secretion after nerve injury. Glia 2019, 67, 78–90. [Google Scholar] [CrossRef]
- Zabala, A.; Vazquez-Villoldo, N.; Rissiek, B.; Gejo, J.; Martin, A.; Palomino, A.; Perez-Samartin, A.; Pulagam, K.R.; Lukowiak, M.; Capetillo-Zarate, E.; et al. P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis. EMBO Mol. Med. 2018, 10. [Google Scholar] [CrossRef]
- Jurga, A.M.; Piotrowska, A.; Makuch, W.; Przewlocka, B.; Mika, J. Blockade of P2X4 Receptors Inhibits Neuropathic Pain-Related Behavior by Preventing MMP-9 Activation and, Consequently, Pronociceptive Interleukin Release in a Rat Model. Front. Pharmacol. 2017, 8, 48. [Google Scholar] [CrossRef] [Green Version]
- Domercq, M.; Matute, C. Targeting P2X4 and P2X7 receptors in multiple sclerosis. Curr. Opin. Pharmacol. 2019, 47, 119–125. [Google Scholar] [CrossRef]
- Ledderose, C.; Liu, K.; Kondo, Y.; Slubowski, C.J.; Dertnig, T.; Denicolo, S.; Arbab, M.; Hubner, J.; Konrad, K.; Fakhari, M.; et al. Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J. Clin. Investig. 2018, 128, 3583–3594. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Daneman, R.; Prat, A. The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 2015, 7, a020412. [Google Scholar] [CrossRef] [Green Version]
- Hersh, D.S.; Wadajkar, A.S.; Roberts, N.; Perez, J.G.; Connolly, N.P.; Frenkel, V.; Winkles, J.A.; Woodworth, G.F.; Kim, A.J. Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Curr. Pharm. Des. 2016, 22, 1177–1193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, N.; Francis, N.L.; Calvelli, H.R.; Moghe, P.V. Microglia-targeting nanotherapeutics for neurodegenerative diseases. APL Bioeng. 2020, 4, 030902. [Google Scholar] [CrossRef] [PubMed]
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Geladaris, A.; Häusler, D.; Weber, M.S. Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression? Int. J. Mol. Sci. 2021, 22, 3461. https://doi.org/10.3390/ijms22073461
Geladaris A, Häusler D, Weber MS. Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression? International Journal of Molecular Sciences. 2021; 22(7):3461. https://doi.org/10.3390/ijms22073461
Chicago/Turabian StyleGeladaris, Anastasia, Darius Häusler, and Martin S. Weber. 2021. "Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?" International Journal of Molecular Sciences 22, no. 7: 3461. https://doi.org/10.3390/ijms22073461