TRR 43: The Brain as a Target of Inflammatory Processes
Final Report Abstract
During its two funding periods, the focus of the Collaborative Research Centre TRR 43 (SFB TRR 43) was to substantiate the hypothesis that immune actions are not only involved in prototypical inflammatory brain diseases such as multiple sclerosis (MS) or encephalitides, but also play an important role in the pathogenesis and pathology of central nervous system (CNS) disorders that are generally considered to be primarily noninflammatory, such as stroke, brain tumors and neurodegenerative disorders. In any of these conditions or disorders, immune cells interact with cells of the nervous system via complex signalling cascades. Besides local cross talk between cells of the nervous and the immune systems, there is increasing evidence that CNS alterations also impact systemic immune responses which in turn may facilitate systemic infections or protect CNS tissue by modulating local CNS actions. Although the initiating events may differ considerably between various CNS diseases, they seem, at least in some instances, to utilize common pathways for the cross talk between the immune and the nervous systems. Deciphering these common - or divergent - pathways was a common denominator for the research of the SFB TRR 43 consortium. While insights into immune functions in certain CNS diseases have already opened up new avenues for preventing or treating these diseases, the SFB TRR 43 envisaged transferring knowledge of immune actions in a given CNS disease to CNS disorders with different origins but similar immune actions. Recent insights have led to a discrimination of CNS disorders as having either an innate-immune or an adaptive-immune component. The translational implication of this distinction will be a therapeutic focus on the respective immune process active in the disease; it is noteworthy that it does not matter whether the immune contribution is primary and disease-causing or secondary and disease-maintaining or - exacerbating. Our collaborative efforts have resulted in the description and characterisation of hitherto unknown roles of both the innate and the adaptive immune system in various CNS conditions or disorders. A few of the “highlights” include the delineation of new pathophysiological aspects of myeloid cells/microglia in neurodegenerative settings such as Alzheimer’s disease (AD) and also in stroke, subarachnoidal hemorrhage and brain tumors, as well as the finding that microRNA can act as signal molecules and thus promote neurodegeneration. We also discovered new mechanisms relevant to inflammatory demyelinating diseases with respect to myelin assembly, the support of axonal energy metabolism by myelinating oligodendrocytes and the cure of hypomyelination by neuroinflammation-dependent transfer of dietary cholesterol. Data provided by SFB TRR 43 principle investigators also enabled a better understanding of crucial steps involved in the initiation of disease-inducing T cells and their recruitment to and interactions within the brain in CNS autoimmunity, thus contributing to a better understanding of the pathogenesis and disease progression in MS and neuromyelitis optica. Moreover, principle investigators of the SFB TRR 43 provided first evidence for a therapeutic intervention in AD, utilizing blockers against a defined immune molecule, namely interleukin (IL)-12 and -23, which appears to be a promising target in AD. During the second funding period, the SFB TRR 43 researchers from Berlin and Göttingen profited from the established close ties and synergistic cooperations, thus considerably expanding the existing joint research. By combining the efforts of clinicians and basic scientists, among others neuroimmunologists and neurobiologists, in a network approach, the SFB TRR 43 consortium has taken up the challenges of the emerging field of translational research. In addition, the SFB TRR 43 has served to further shape the profile and scope of the ongoing neuroimmunological research at both sites insofar as our research focused on processes inside rather than outside the CNS. Particularly in light of emerging novel neuroimmunological concepts to distinguish immune driven CNS diseases mainly by their innate-immune or adaptive-immune predominance, our initial organizational basis for the SFB TRR 43 with its focus on the interaction of the immune system with the nervous system can be seen in retrospect as visionary and imaginative.
Publications
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Lehmann SM, Krüger C, Park B, Derkow K, Rosenberger K, Baumgart J, Trimbuch T, Eom G, Hinz M, Kaul D, Habbel P, Kälin R, Franzoni E, Rybak A, Nguyen D, Veh R, Ninnemann O, Peters O, Nitsch R, Heppner FL, Golenbock DT, Schott E, Ploegh HL, Wulczyn FG, Lehnardt S
(See online at https://doi.org/10.1038/nn.3113) - (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nature medicine 18:1812-1819
Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O, Winter Y, Becher B, Heppner FL
(See online at https://doi.org/10.1038/nm.2965) - (2012) T cells become licensed in the lung to enter the central nervous system. Nature 488:675-679
Odoardi F, Sie C, Streyl K, Ulaganathan VK, Schlager C, Lodygin D, Heckelsmiller K, Nietfeld W, Ellwart J, Klinkert WE, Lottaz C, Nosov M, Brinkmann V, Spang R, Lehrach H, Vingron M, Wekerle H, Flügel-Koch C, Flügel A
(See online at https://doi.org/10.1038/nature11337) - (2013) A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity. Nat Med 19:784-790
Lodygin D, Odoardi F, Schlager C, Korner H, Kitz A, Nosov M, van den Brandt J, Reichardt HM, Haberl M, Flugel A
(See online at https://doi.org/10.1038/nm.3182) - (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nature reviews Neuroscience 15:300-312
Prinz M, Priller J
(See online at https://doi.org/10.1038/nrn3722) - (2014) The subpopulation of microglia sensitive to neurotransmitters/neurohormones is modulated by stimulation with LPS, interferon-gamma, and IL-4. Glia 62:667-679
Pannell M, Szulzewsky F, Matyash V, Wolf SA, Kettenmann H
(See online at https://doi.org/10.1002/glia.22633) - (2015) Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. The Journal of clinical investigation 125:4196-4211
rehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, Montealegre G, Biancotto A, Reinhardt A, Almeida de Jesus A, Pelletier M, Tsai WL, Remmers EF, Kardava L, Hill S, Kim H, Lachmann HJ, Megarbane A, Chae JJ, Brady J, Castillo RD, Brown D, Casano AV, Gao L, Chapelle D, Huang Y, Stone D, Chen Y, Sotzny F, Lee C-CR, Kastner DL, Torrelo A, Zlotogorski A, Moir S, Gadina M, McCoy P, Wesley R, Rother K, Hildebrand PW, Brogan P, Krüger E, Aksentijevich I, Goldbach-Mansky R
(See online at https://doi.org/10.1172/jci81260) - (2015) Cell type- and brain region-resolved mouse brain proteome. Nature neuroscience 18:1819-1831
Sharma K, Schmitt S, Bergner CG, Tyanova S, Kannaiyan N, Manrique-Hoyos N, Kongi K, Cantuti L, Hanisch UK, Philips MA, Rossner MJ, Mann M, Simons M
(See online at https://doi.org/10.1038/nn.4160) - (2015) Extensive acute axonal damage in pediatric multiple sclerosis lesions. Annals of neurology 77:655-667
Pfeifenbring S, Bunyan RF, Metz I, Rover C, Huppke P, Gartner J, Lucchinetti CF, Bruck W
(See online at https://doi.org/10.1002/ana.24364) - (2015) Immune attack: the role of inflammation in Alzheimer disease. Nature reviews Neuroscience 16:358-372
Heppner FL, Ransohoff RM, Becher B
(See online at https://doi.org/10.1038/nrn3880) - (2015) Intrathecal heat shock protein 60 mediates neurodegeneration and demyelination in the CNS through a TLR4- and MyD88-dependent pathway. Molecular neurodegeneration 10:5
Rosenberger K, Dembny P, Derkow K, Engel O, Kruger C, Wolf SA, Kettenmann H, Schott E, Meisel A, Lehnardt S
(See online at https://doi.org/10.1186/s13024-015-0003-1) - (2015) Microglia inflict delayed brain injury after subarachnoid hemorrhage. Acta neuropathologica 130:215-231
Schneider UC, Davids AM, Brandenburg S, Muller A, Elke A, Magrini S, Atangana E, Turkowski K, Finger T, Gutenberg A, Gehlhaar C, Bruck W, Heppner FL, Vajkoczy P
(See online at https://doi.org/10.1007/s00401-015-1440-1) - (2015) Vascular signal transducer and activator of transcription-3 promotes angiogenesis and neuroplasticity long-term after stroke. Circulation 131:1772-1782
Hoffmann CJ, Harms U, Rex A, Szulzewsky F, Wolf SA, Grittner U, Lattig-Tunnemann G, Sendtner M, Kettenmann H, Dirnagl U, Endres M, Harms C
(See online at https://doi.org/10.1161/circulationaha.114.013003) - (2016) Age-related myelin degradation burdens the clearance function of microglia during aging. Nature neuroscience 19:995-998
Safaiyan S, Kannaiyan N, Snaidero N, Brioschi S, Biber K, Yona S, Edinger AL, Jung S, Rossner MJ, Simons M
(See online at https://doi.org/10.1038/nn.4325) - (2016) Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease. Proc Natl Acad Sci U S A 113:3323-3328
Flach AC, Litke T, Strauss J, Haberl M, Gomez CC, Reindl M, Saiz A, Fehling HJ, Wienands J, Odoardi F, Lühder F, Flügel A
(See online at https://doi.org/10.1073/pnas.1519608113) - (2016) Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530:349-353
Schläger C, Korner H, Krueger M, Vidoli S, Haberl M, Mielke D, Brylla E, Issekutz T, Cabanas C, Nelson PJ, Ziemssen T, Rohde V, Bechmann I, Lodygin D, Odoardi F, Flügel A
(See online at https://doi.org/10.1038/nature16939) - (2016) Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism. Neuron 91:119-132
Saab AS, Tzvetavona ID, Trevisiol A, Baltan S, Dibaj P, Kusch K, Möbius W, Goetze B, Jahn HM, Huang W, Steffens H, Schomburg ED, Pérez-Samartín A, Pérez-Cerdá F, Bakhtiari D, Matute C, Löwel S, Griesinger C, Hirrlinger J, Kirchhoff F, Nave KA
(See online at https://doi.org/10.1016/j.neuron.2016.05.016) - (2016) Origin, fate and dynamics of macrophages at central nervous system interfaces. Nature immunology 17:797-805
Goldmann T, Wieghofer P, Costa Jordao MJ, Prutek F, Hagemeyer N, Frenzel K, Amann L, Staszewski O, Kierdorf K, Krueger M, Locatelli G, Hochgarner H, Zeiser R, Epelmann S, Geissmann F, Priller J, Rossi F, Bechmann I, Kerschensteiner M, Linnarsson S, Jung S, Prinz M
(See online at https://doi.org/10.1038/ni.3423) - (2016) Partial loss of VE-cadherin improves long-term outcome and cerebral blood flow after transient brain ischemia in mice. BMC neurology 16:144
Gertz K, Kronenberg G, Uhlemann R, Prinz V, Marquina R, Corada M, Dejana E, Endres M
(See online at https://doi.org/10.1186/s12883-016-0670-8) - (2016) The subpopulation of microglia expressing functional muscarinic acetylcholine receptors expands in stroke and Alzheimer's disease. Brain structure & function 221:1157-1172
Pannell M, Meier MA, Szulzewsky F, Matyash V, Endres M, Kronenberg G, Prinz V, Waiczies S, Wolf SA, Kettenmann H
(See online at https://doi.org/10.1007/s00429-014-0962-y) - (2017) Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis. Acta neuropathologica
Lagumersindez-Denis N, Wrzos C, Mack M, Winkler A, van der Meer F, Reinert MC, Hollasch H, Flach A, Brühl H, Cullen E, Schlumbohm C, Fuchs E, Linington C, Barrantes-Freer A, Metz I, Wegner C, Liebetanz D, Prinz M, Brück W, Stadelmann C# and Nessler S
(See online at https://doi.org/10.1007/s00401-017-1706-x) - (2017) Intravascular Inflammation Triggers Intracerebral Activated Microglia and Contributes to Secondary Brain Injury After Experimental Subarachnoid Hemorrhage (eSAH). Translational stroke research 8:144-156
Atangana E, Schneider UC, Blecharz K, Magrini S, Wagner J, Nieminen-Kelha M, Kremenetskaia I, Heppner FL, Engelhardt B, Vajkoczy P
(See online at https://doi.org/10.1007/s12975-016-0485-3) - (2017) Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy. eLife 6: e23332
Kleinecke S, Richert S, de Hoz L, Brugger B, Kungl T, Asadollahi E, Quintes S, Blanz J, McGonigal R, Naseri K, Sereda MW, Sachsenheimer T, Luchtenborg C, Mobius W, Willison H, Baes M, Nave KA, Kassmann CM
(See online at https://doi.org/10.7554/elife.23332)
