@article{BrosinskyLeisterChengetal.2022, author = {Brosinsky, Paulin and Leister, Hanna and Cheng, Nan and Varelas, Xaralabos and Visekruna, Alexander and Luu, Maik}, title = {Verteporfin protects against Th17 cell-mediated EAE independently of YAP inhibition}, series = {European Journal of Immunology}, volume = {52}, journal = {European Journal of Immunology}, number = {9}, doi = {10.1002/eji.202149564}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287234}, pages = {1523 -- 1526}, year = {2022}, abstract = {The known YAP inhibitor verteporfin is capable of repressing IL-17A production in Th17 cells. However, this effect is mediated independently of YAP and can ameliorate Th17-mediated experimental autoimmune encephalomyelitis (EAE) upon in vivo administration. The data suggest verteprofin's mode of action for the design of novel therapeutic autoimmune disease intervention.}, language = {en} } @article{RajendranRajendranGiraldoVelasquezetal.2021, author = {Rajendran, Ranjithkumar and Rajendran, Vinothkumar and Giraldo-Velasquez, Mario and Megalofonou, Fevronia-Foivi and Gurski, Fynn and Stadelmann, Christine and Karnati, Srikanth and Berghoff, Martin}, title = {Oligodendrocyte-specific deletion of FGFR1 reduces cerebellar inflammation and neurodegeneration in MOG\(_{35-55}\)-induced EAE}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {17}, issn = {1422-0067}, doi = {10.3390/ijms22179495}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284296}, year = {2021}, abstract = {Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1\(^{ind-/-}\) was achieved by tamoxifen application, EAE was induced using the MOG\(_{35-55}\) peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1\(^{ind-/-}\) mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1\(^{ind-/-}\)mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1\(^{ind-/-}\) mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1\(^{ind-/-}\) mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.}, language = {en} } @article{BittnerBobakHofmannetal.2015, author = {Bittner, Stefan and Bobak, Nicole and Hofmann, Majella-Sophie and Schuhmann, Michael K. and Ruck, Tobias and G{\"o}bel, Kerstin and Br{\"u}ck, Wolfgang and Wiendl, Heinz and Meuth, Sven G.}, title = {Murine K\(_{2P}\)5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K\(_{2P}\)3.1-and K\(_{V}\)1.3-Dependent Mechanisms}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160816880}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151454}, pages = {16880 -- 16896}, year = {2015}, abstract = {Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K\(_{2P}\)5.1(TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K\(_{2P}\)5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K\(_{2P}\)5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K\(_{2P}\)5.1 knockout (K\(_{2P}\)5.1\(^{-/-}\) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K\(_{2P}\)5.1\(^{-/-}\) mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K\(_{2P}\)3.1 and K\(_{V}\)1.3 seems to counterbalance the deletion of K\(_{2P}\)5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K\(_{2P}\)5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K\(_{2P}\)5.1-targeting drugs.}, language = {en} } @article{RajendranRajendranGuptaetal.2022, author = {Rajendran, Ranjithkumar and Rajendran, Vinothkumar and Gupta, Liza and Shirvanchi, Kian and Schunin, Darja and Karnati, Srikanth and Giraldo-Vel{\´a}squez, Mario and Berghoff, Martin}, title = {Interferon beta-1a versus combined interferon beta-1a and oligodendrocyte-specific FGFR1 deletion in experimental autoimmune encephalomyelitis}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {20}, issn = {1422-0067}, doi = {10.3390/ijms232012183}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290401}, year = {2022}, abstract = {Recombinant beta interferons-1 (IFNβ-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNβ-1a/b has moderate effects on the prevention of relapses and slowing of disease progression. Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known to play a key role in the pathology of MS and its model EAE. To investigate the effects of short-term treatment with s.c. IFNβ-1a versus the combined application of s.c. IFNβ-1a and oligodendrocyte-specific deletion of FGFR1 (Fgfr1\(^{ind-/-}\) mice) in MOG\(_{35-55}\)-induced EAE. IFNβ-1a (30 mg/kg) was applied s.c. from days 0-7 p.i. of EAE in controls and Fgfr1\(^{ind-/-}\) mice. FGFR signaling proteins associated with inflammation/degeneration in MS/EAE were analyzed by western blot in the spinal cord. Further, FGFR1 in Oli-neu oligodendrocytes were inhibited by PD166866 and treated with IFNβ-1a (400 ng/mL). Application of IFNβ-1a over 8 days resulted in less symptoms only at the peak of disease (days 9-11) compared to controls. Application of IFNβ-1a in Fgfr1\(^{ind-/-}\) mice resulted in less symptoms primarily in the chronic phase of EAE. Fgfr1\(^{ind-/-}\) mice treated with IFNβ-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNβ-1a also showed an increased expression of pERK and BDNF/TrkB. These data suggest that the beneficial effects in the chronic phase of EAE and on signaling molecules associated with ERK and BDNF expression are caused by the modulation of FGFR1 and not by interferon beta-1a. FGFR may be a potential target for therapy in MS.}, language = {en} } @article{RajendranBoettigerStadelmannetal.2021, author = {Rajendran, Ranjithkumar and B{\"o}ttiger, Gregor and Stadelmann, Christine and Karnati, Srikanth and Berghoff, Martin}, title = {FGF/FGFR pathways in multiple sclerosis and in its disease models}, series = {Cells}, volume = {10}, journal = {Cells}, number = {4}, issn = {2073-4409}, doi = {10.3390/cells10040884}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236594}, year = {2021}, abstract = {Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)\(_{35-55}\)-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS.}, language = {en} } @article{BailNotzRovitusoetal.2017, author = {Bail, Kathrin and Notz, Quirin and Rovituso, Damiano M. and Schampel, Andrea and Wunsch, Marie and Koeniger, Tobias and Schropp, Verena and Bharti, Richa and Scholz, Claus-Juergen and Foerstner, Konrad U. and Kleinschnitz, Christoph and Kuerten, Stefanie}, title = {Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis.}, series = {Journal of Neuroinflammation}, volume = {14}, journal = {Journal of Neuroinflammation}, number = {148}, doi = {10.1186/s12974-017-0924-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157869}, year = {2017}, abstract = {Background: MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS). Methods: MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P\(_{1}\) receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro. Results: FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220\(^{+}\) B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs. Conclusions: The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.}, language = {en} } @article{SchampelKuerten2017, author = {Schampel, Andrea and Kuerten, Stefanie}, title = {Danger: high voltage - the role of voltage-gated calcium channels in central nervous system pathology}, series = {Cells}, volume = {6}, journal = {Cells}, number = {4}, doi = {10.3390/cells6040043}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172653}, year = {2017}, abstract = {Voltage-gated calcium channels (VGCCs) are widely distributed within the central nervous system (CNS) and presumed to play an important role in the pathophysiology of a broad spectrum of CNS disorders including Alzheimer's and Parkinson's disease as well as multiple sclerosis. Several calcium channel blockers have been in clinical practice for many years so that their toxicity and side effects are well studied. However, these drugs are primarily used for the treatment of cardiovascular diseases and most if not all effects on brain functions are secondary to peripheral effects on blood pressure and circulation. While the use of calcium channel antagonists for the treatment of CNS diseases therefore still heavily depends on the development of novel strategies to specifically target different channels and channel subunits, this review is meant to provide an impulse to further emphasize the importance of future research towards this goal.}, language = {en} } @article{SimonIpekHomolaetal.2018, author = {Simon, Micha and Ipek, Rojda and Homola, Gy{\"o}rgy A. and Rovituso, Damiano M. and Schampel, Andrea and Kleinschnitz, Christoph and Kuerten, Stefanie}, title = {Anti-CD52 antibody treatment depletes B cell aggregates in the central nervous system in a mouse model of multiple sclerosis}, series = {Journal of Neuroinflammation}, volume = {15}, journal = {Journal of Neuroinflammation}, number = {225}, doi = {10.1186/s12974-018-1263-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176120}, year = {2018}, abstract = {Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) for which several new treatment options were recently introduced. Among them is the monoclonal anti-CD52 antibody alemtuzumab that depletes mainly B cells and T cells in the immune periphery. Considering the ongoing controversy about the involvement of B cells and in particular the formation of B cell aggregates in the brains of progressive MS patients, an in-depth understanding of the effects of anti-CD52 antibody treatment on the B cell compartment in the CNS itself is desirable. Methods: We used myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice as B cell-dependent model of MS. Mice were treated intraperitoneally either at the peak of EAE or at 60 days after onset with 200 μg murine anti-CD52 vs. IgG2a isotype control antibody for five consecutive days. Disease was subsequently monitored for 10 days. The antigen-specific B cell/antibody response was measured by ELISPOT and ELISA. Effects on CNS infiltration and B cell aggregation were determined by immunohistochemistry. Neurodegeneration was evaluated by Luxol Fast Blue, SMI-32, and Olig2/APC staining as well as by electron microscopy and phosphorylated heavy neurofilament serum ELISA. Results: Treatment with anti-CD52 antibody attenuated EAE only when administered at the peak of disease. While there was no effect on the production of MP4-specific IgG, the treatment almost completely depleted CNS infiltrates and B cell aggregates even when given as late as 60 days after onset. On the ultrastructural level, we observed significantly less axonal damage in the spinal cord and cerebellum in chronic EAE after anti-CD52 treatment. Conclusion: Anti-CD52 treatment abrogated B cell infiltration and disrupted existing B cell aggregates in the CNS.}, language = {en} }