TY  - JOUR
A1  - Hollmann, Claudia
A1  - Werner, Sandra
A1  - Avota, Elita
A1  - Reuter, Dajana
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Becker, Katrin Anne
A1  - Schneider-Schaulies, Jürgen
A1  - Beyersdorf, Niklas
T1  - Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4(+) Conventional versus Foxp3(+) Regulatory T Cells
JF  - The journal of immunology
N2  - CD4(+) Foxp3(+) regulatory T cells (Tregs) depend on CD28 signaling for their survival and function, a receptor that has been previously shown to activate the acid sphingomyelinase (Asm)/ceramide system. In this article, we show that the basal and CD28-induced Asm activity is higher in Tregs than in conventional CD4(+) T cells (Tconvs) of wild-type (wt) mice. In Asm-deficient (Smpd1(-/-); Asm(-/-)) mice, as compared with wt mice, the frequency of Tregs among CD4(+) T cells, turnover of the effector molecule CTLA-4, and their suppressive activity in vitro were increased. The biological significance of these findings was confirmed in our Treg-sensitive mouse model of measles virus (MV) CNS infection, in which we observed more infected neurons and less MV-specific CD8(+) T cells in brains of Asm(-/-) mice compared with wt mice. In addition to genetic deficiency, treatment of wt mice with the Asm inhibitor amitriptyline recapitulated the phenotype of Asm-deficient mice because it also increased the frequency of Tregs among CD4(+) T cells. Reduced absolute cell numbers of Tconvs after inhibitor treatment in vivo and extensive in vitro experiments revealed that Tregs are more resistant toward Asm inhibitor-induced cell death than Tconvs. Mechanistically, IL-2 was capable of providing crucial survival signals to the Tregs upon inhibitor treatment in vitro, shifting the Treg/Tconv ratio to the Treg side. Thus, our data indicate that Asm-inhibiting drugs should be further evaluated for the therapy of inflammatory and autoimmune disorders.
Y1  - 2016
U6  - https://doi.org/10.4049/jimmunol.1600691
SN  - 0022-1767
SN  - 1550-6606
VL  - 197
SP  - 3130
EP  - 3141
PB  - American Assoc. of Immunologists
CY  - Bethesda
ER  - 
TY  - GEN
A1  - Hollmann, C.
A1  - Reuter, D.
A1  - Werner, S.
A1  - Avota, Elita
A1  - Mueller, N.
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Becker, Katrin Anne
A1  - Gulbins, Erich
A1  - Schneider-Schaulies, Jürgen
A1  - Beyersdorf, Niklas
T1  - Pharmacological inhibition of acid sphingomyelinase or genetic ablation enhances CD4(+) Foxp3(+) regulatory T cell activity
T2  - European journal of immunology
Y1  - 2016
SN  - 0014-2980
SN  - 1521-4141
VL  - 46
SP  - 14
EP  - 14
PB  - Wiley-Blackwell
CY  - Hoboken
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  - https://doi.org/10.3389/fcell.2019.00218
SN  - 2296-634X
VL  - 7
PB  - Frontiers Research Foundation
CY  - Lausanne
ER  -