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  - 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  -