TY - JOUR A1 - Wiese, Teresa A1 - Dennstädt, Fabio A1 - Hollmann, Claudia A1 - Stonawski, Saskia A1 - Wurst, Catherina A1 - Fink, Julian A1 - Gorte, Erika A1 - Mandasari, Putri A1 - Domschke, Katharina A1 - Hommers, Leif A1 - Vanhove, Bernard A1 - Schumacher, Fabian A1 - Kleuser, Burkard A1 - Seibel, Jürgen A1 - Rohr, Jan A1 - Buttmann, Mathias A1 - Menke, Andreas A1 - Schneider-Schaulies, Jürgen A1 - Beyersdorf, Niklas T1 - Inhibition of acid sphingomyelinase increases regulatory T cells in humans JF - Brain Communications N2 - Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro. KW - acid sphingomyelinase KW - antidepressants KW - major depression KW - regulatory T cells KW - sphingolipids Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259868 VL - 3 IS - 2 ER - TY - JOUR A1 - Grafen, Anika A1 - Schumacher, Fabian A1 - Chithelen, Janice A1 - Kleuser, Burkhard A1 - Beyersdorf, Niklas A1 - Schneider-Schaulies, Jürgen T1 - Use of acid ceramidase and sphingosine kinase inhibitors as antiviral compounds against measles virus infection of lymphocytes in vitro JF - Frontiers in Cell and Developmental Biology N2 - As structural membrane components and signaling effector molecules sphingolipids influence a plethora of host cell functions, and by doing so also the replication of viruses. Investigating the effects of various inhibitors of sphingolipid metabolism in primary human peripheral blood lymphocytes (PBL) and the human B cell line BJAB we found that not only the sphingosine kinase (SphK) inhibitor SKI-II, but also the acid ceramidase inhibitor ceranib-2 efficiently inhibited measles virus (MV) replication. Virus uptake into the target cells was not grossly altered by the two inhibitors, while titers of newly synthesized MV were reduced by approximately 1 log (90%) in PBL and 70–80% in BJAB cells. Lipidomic analyses revealed that in PBL SKI-II led to increased ceramide levels, whereas in BJAB cells ceranib-2 increased ceramides. SKI-II treatment decreased sphingosine-1-phosphate (S1P) levels in PBL and BJAB cells. Furthermore, we found that MV infection of lymphocytes induced a transient (0.5–6 h) increase in S1P, which was prevented by SKI-II. Investigating the effect of the inhibitors on the metabolic (mTORC1) activity we found that ceranib-2 reduced the phosphorylation of p70 S6K in PBL, and that both inhibitors, ceranib-2 and SKI-II, reduced the phosphorylation of p70 S6K in BJAB cells. As mTORC1 activity is required for efficient MV replication, this effect of the inhibitors is one possible antiviral mechanism. In addition, reduced intracellular S1P levels affect a number of signaling pathways and functions including Hsp90 activity, which was reported to be required for MV replication. Accordingly, we found that pharmacological inhibition of Hsp90 with the inhibitor 17-AAG strongly impaired MV replication in primary PBL. Thus, our data suggest that treatment of lymphocytes with both, acid ceramidase and SphK inhibitors, impair MV replication by affecting a number of cellular activities including mTORC1 and Hsp90, which alter the metabolic state of the cells causing a hostile environment for the virus. KW - measles virus KW - sphingolipids KW - acid ceramidase KW - acid ceramidase inhibitor ceranib-2 KW - sphingosine kinase KW - sphingosine kinase inhibitor SKI-II Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196099 SN - 2296-634X VL - 7 IS - 218 ER - TY - JOUR A1 - Hollmann, Claudia A1 - Wiese, Teresa A1 - Dennstädt, Fabio A1 - Fink, Julian A1 - Schneider-Schaulies, Jürgen A1 - Beyersdorf, Niklas T1 - Translational approaches targeting ceramide generation from sphingomyelin in T cells to modulate immunity in humans JF - Frontiers in Immunology N2 - In T cells, as in all other cells of the body, sphingolipids form important structural components of membranes. Due to metabolic modifications, sphingolipids additionally play an active part in the signaling of cell surface receptors of T cells like the T cell receptor or the co-stimulatory molecule CD28. Moreover, the sphingolipid composition of their membranes crucially affects the integrity and function of subcellular compartments such as the lysosome. Previously, studying sphingolipid metabolism has been severely hampered by the limited number of analytical methods/model systems available. Besides well-established high resolution mass spectrometry new tools are now available like novel minimally modified sphingolipid subspecies for click chemistry as well as recently generated mouse mutants with deficiencies/overexpression of sphingolipid-modifying enzymes. Making use of these tools we and others discovered that the sphingolipid sphingomyelin is metabolized to ceramide to different degrees in distinct T cell subpopulations of mice and humans. This knowledge has already been translated into novel immunomodulatory approaches in mice and will in the future hopefully also be applicable to humans. In this paper we are, thus, summarizing the most recent findings on the impact of sphingolipid metabolism on T cell activation, differentiation, and effector functions. Moreover, we are discussing the therapeutic concepts arising from these insights and drugs or drug candidates which are already in clinical use or could be developed for clinical use in patients with diseases as distant as major depression and chronic viral infection. KW - sphingolipids KW - CD4+ T cells KW - regulatory T cells (Treg) KW - CD8+ T cells KW - anti-depressant drug Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198806 SN - 1664-3224 VL - 10 IS - 2363 ER - TY - JOUR A1 - Avota, Elita A1 - Bodem, Jochen A1 - Chithelen, Janice A1 - Mandasari, Putri A1 - Beyersdorf, Niklas A1 - Schneider-Schaulies, Jürgen T1 - The Manifold Roles of Sphingolipids in Viral Infections JF - Frontiers in Physiology N2 - Sphingolipids are essential components of eukaryotic cells. In this review, we want to exemplarily illustrate what is known about the interactions of sphingolipids with various viruses at different steps of their replication cycles. This includes structural interactions during entry at the plasma membrane or endosomal membranes, early interactions leading to sphingolipid-mediated signal transduction, interactions with internal membranes and lipids during replication, and interactions during virus assembly and budding. Targeted interventions in sphingolipid metabolism – as far as they can be tolerated by cells and organisms – may open novel possibilities to support antiviral therapies. Human immunodeficiency virus type 1 (HIV-1) infections have intensively been studied, but for other viral infections, such as influenza A virus (IAV), measles virus (MV), hepatitis C virus (HCV), dengue virus, Ebola virus, and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), investigations are still in their beginnings. As many inhibitors of sphingolipid metabolism are already in clinical use against other diseases, repurposing studies for applications in some viral infections appear to be a promising approach. KW - sphingolipid KW - ceramide KW - sphingosine-1-phosphate KW - plasma membrane KW - virus entry KW - virus replication KW - virus budding Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246975 SN - 1664-042X VL - 12 ER - TY - JOUR A1 - Eder, Sascha A1 - Hollmann, Claudia A1 - Mandasari, Putri A1 - Wittmann, Pia A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Fink, Julian A1 - Seibel, Jürgen A1 - Schneider-Schaulies, Jürgen A1 - Stigloher, Christian A1 - Beyersdorf, Niklas A1 - Dembski, Sofia T1 - Synthesis and characterization of ceramide-containing liposomes as membrane models for different T cell subpopulations JF - Journal of Functional Biomaterials N2 - A fine balance of regulatory (T\(_{reg}\)) and conventional CD4\(^+\) T cells (T\(_{conv}\)) is required to prevent harmful immune responses, while at the same time ensuring the development of protective immunity against pathogens. As for many cellular processes, sphingolipid metabolism also crucially modulates the T\(_{reg}\)/T\(_{conv}\) balance. However, our understanding of how sphingolipid metabolism is involved in T cell biology is still evolving and a better characterization of the tools at hand is required to advance the field. Therefore, we established a reductionist liposomal membrane model system to imitate the plasma membrane of mouse T\(_{reg}\) and T\(_{conv}\) with regards to their ceramide content. We found that the capacity of membranes to incorporate externally added azide-functionalized ceramide positively correlated with the ceramide content of the liposomes. Moreover, we studied the impact of the different liposomal preparations on primary mouse splenocytes in vitro. The addition of liposomes to resting, but not activated, splenocytes maintained viability with liposomes containing high amounts of C\(_{16}\)-ceramide being most efficient. Our data thus suggest that differences in ceramide post-incorporation into T\(_{reg}\) and T\(_{conv}\) reflect differences in the ceramide content of cellular membranes. KW - liposome KW - ceramide KW - cell membrane model Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286130 SN - 2079-4983 VL - 13 IS - 3 ER -