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  - Bernt, Alexander
A1  - Rangrez, Ashraf Y.
A1  - Eden, Matthias
A1  - Jungmann, Andreas
A1  - Katz, Sylvia
A1  - Rohr, Claudia
A1  - Müller, Oliver J.
A1  - Katus, Hugo A.
A1  - Sossalla, Samuel T.
A1  - Williams, Tatjana
A1  - Ritter, Oliver
A1  - Frank, Derk
A1  - Frey, Norbert
T1  - Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy
JF  - Scientific Reports
N2  - The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10\(^{7}\) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.
KW  - Calcineurin-NFATsignaling
KW  - activation
KW  - SUMO2
KW  - cardiac hypertrophy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167525
VL  - 6
IS  - 35758
ER  -