TY  - JOUR
A1  - Haake, Markus
A1  - Haack, Beatrice
A1  - Schäfer, Tina
A1  - Harter, Patrick N.
A1  - Mattavelli, Greta
A1  - Eiring, Patrick
A1  - Vashist, Neha
A1  - Wedekink, Florian
A1  - Genssler, Sabrina
A1  - Fischer, Birgitt
A1  - Dahlhoff, Julia
A1  - Mokhtari, Fatemeh
A1  - Kuzkina, Anastasia
A1  - Welters, Marij J. P.
A1  - Benz, Tamara M.
A1  - Sorger, Lena
A1  - Thiemann, Vincent
A1  - Almanzar, Giovanni
A1  - Selle, Martina
A1  - Thein, Klara
A1  - Späth, Jacob
A1  - Gonzalez, Maria Cecilia
A1  - Reitinger, Carmen
A1  - Ipsen-Escobedo, Andrea
A1  - Wistuba-Hamprecht, Kilian
A1  - Eichler, Kristin
A1  - Filipski, Katharina
A1  - Zeiner, Pia S.
A1  - Beschorner, Rudi
A1  - Goedemans, Renske
A1  - Gogolla, Falk Hagen
A1  - Hackl, Hubert
A1  - Rooswinkel, Rogier W.
A1  - Thiem, Alexander
A1  - Romer Roche, Paula
A1  - Joshi, Hemant
A1  - Pühringer, Dirk
A1  - Wöckel, Achim
A1  - Diessner, Joachim E.
A1  - Rüdiger, Manfred
A1  - Leo, Eugen
A1  - Cheng, Phil F.
A1  - Levesque, Mitchell P.
A1  - Goebeler, Matthias
A1  - Sauer, Markus
A1  - Nimmerjahn, Falk
A1  - Schuberth-Wagner, Christine
A1  - Felten, Stefanie von
A1  - Mittelbronn, Michel
A1  - Mehling, Matthias
A1  - Beilhack, Andreas
A1  - van der Burg, Sjoerd H.
A1  - Riedel, Angela
A1  - Weide, Benjamin
A1  - Dummer, Reinhard
A1  - Wischhusen, Jörg
T1  - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
JF  - Nature Communications
N2  - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
KW  - cancer microenvironment
KW  - immunotherapy
KW  - T cells
KW  - tumour immunology
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333
VL  - 14
ER  - 
TY  - JOUR
A1  - Brenner, Daniela
A1  - Geiger, Nina
A1  - Schlegel, Jan
A1  - Diesendorf, Viktoria
A1  - Kersting, Louise
A1  - Fink, Julian
A1  - Stelz, Linda
A1  - Schneider-Schaulies, Sibylle
A1  - Sauer, Markus
A1  - Bodem, Jochen
A1  - Seibel, Jürgen
T1  - Azido-ceramides, a tool to analyse SARS-CoV-2 replication and inhibition — SARS-CoV-2 is inhibited by ceramides
JF  - International Journal of Molecular Sciences
N2  - Recently, we have shown that C6-ceramides efficiently suppress viral replication by trapping the virus in lysosomes. Here, we use antiviral assays to evaluate a synthetic ceramide derivative α-NH2-ω-N3-C6-ceramide (AKS461) and to confirm the biological activity of C6-ceramides inhibiting SARS-CoV-2. Click-labeling with a fluorophore demonstrated that AKS461 accumulates in lysosomes. Previously, it has been shown that suppression of SARS-CoV-2 replication can be cell-type specific. Thus, AKS461 inhibited SARS-CoV-2 replication in Huh-7, Vero, and Calu-3 cells up to 2.5 orders of magnitude. The results were confirmed by CoronaFISH, indicating that AKS461 acts comparable to the unmodified C6-ceramide. Thus, AKS461 serves as a tool to study ceramide-associated cellular and viral pathways, such as SARS-CoV-2 infections, and it helped to identify lysosomes as the central organelle of C6-ceramides to inhibit viral replication.
KW  - ceramides
KW  - SARS-CoV-2
KW  - azido-ceramides
KW  - sphingolipids
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313581
SN  - 1422-0067
VL  - 24
IS  - 8
ER  - 
TY  - JOUR
A1  - Geiger, Nina
A1  - Kersting, Louise
A1  - Schlegel, Jan
A1  - Stelz, Linda
A1  - Fähr, Sofie
A1  - Diesendorf, Viktoria
A1  - Roll, Valeria
A1  - Sostmann, Marie
A1  - König, Eva-Maria
A1  - Reinhard, Sebastian
A1  - Brenner, Daniela
A1  - Schneider-Schaulies, Sibylle
A1  - Sauer, Markus
A1  - Seibel, Jürgen
A1  - Bodem, Jochen
T1  - The acid ceramidase is a SARS-CoV-2 host factor
JF  - Cells
N2  - SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2–RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor.
KW  - SARS-CoV-2
KW  - ceramides
KW  - ceramidase
KW  - fluoxetine
KW  - acid sphingomyelinase
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286105
SN  - 2073-4409
VL  - 11
IS  - 16
ER  - 
TY  - JOUR
A1  - Haack, Stephanie
A1  - Baiker, Sarah
A1  - Schlegel, Jan
A1  - Sauer, Markus
A1  - Sparwasser, Tim
A1  - Langenhorst, Daniela
A1  - Beyersdorf, Niklas
T1  - Superagonistic CD28 stimulation induces IFN‐γ release from mouse T helper 1 cells in vitro and in vivo
JF  - European Journal of Immunology
N2  - Like human Th1 cells, mouse Th1 cells also secrete IFN‐γ upon stimulation with a superagonistic anti‐CD28 monoclonal antibody (CD28‐SA). Crosslinking of the CD28‐SA via FcR and CD40‐CD40L interactions greatly increased IFN‐γ release. Our data stress the utility of the mouse as a model organism for immune responses in humans.
KW  - CD28
KW  - Th1 cells
KW  - cytokine release
KW  - interferon γ
KW  - Superagonistic antibody
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239028
VL  - 51
IS  - 3
SP  - 738
EP  - 741
ER  - 
TY  - JOUR
A1  - Derakhshani, Shaghayegh
A1  - Kurz, Andreas
A1  - Japtok, Lukasz
A1  - Schumacher, Fabian
A1  - Pilgram, Lisa
A1  - Steinke, Maria
A1  - Kleuser, Burkhard
A1  - Sauer, Markus
A1  - Schneider-Schaulies, Sibylle
A1  - Avota, Elita
T1  - Measles virus infection fosters dendritic cell motility in a 3D environment to enhance transmission to target cells in the respiratory epithelium
JF  - Frontiers in Immunology
N2  - Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit.
KW  - dendritic cell
KW  - cell migration
KW  - measles virus
KW  - 3D tissue model
KW  - sphingosine-1-phosphate
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201818
VL  - 10
IS  - 1294
ER  - 
TY  - JOUR
A1  - Börtlein, Charlene
A1  - Draeger, Annette
A1  - Schoenauer, Roman
A1  - Kuhlemann, Alexander
A1  - Sauer, Markus
A1  - Schneider-Schaulies, Sybille
A1  - Avota, Elita
T1  - The neutral sphingomyelinase 2 is required to polarize and sustain T Cell receptor signaling
JF  - Frontiers in Immunology
N2  - By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca\(^{2+}\) mobilization and T cell proliferation. NSM-deficient T cells lack sustained CD3ζ and ZAP-70 phosphorylation and are unable to polarize and stabilize their microtubular system. We identified PKCζ as the key NSM downstream effector in this second wave of TCR signaling supporting dynamics of microtubule-organizing center (MTOC). Ceramide supplementation rescued PKCζ membrane recruitment and MTOC translocation in NSM-deficient cells. These findings identify the NSM as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components: CD3ζ, Zap70, and PKCζ, and functional immune synapses are organized and stabilized via MTOC polarization.
KW  - neutral sphingomyelinase 2
KW  - T cells
KW  - ceramides
KW  - PKCζ,
KW  - the microtubule-organizing center
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176572
VL  - 9
IS  - 815
ER  -