Inhibition of acid sphingomyelinase increases regulatory T cells in humans

Abstract: 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− CD25high 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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Brain communications. - 3, 2 (2021) , fcab020, ISSN: 2632-1297

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2021
• Creator: Wiese, Teresa ; Dennstädt, Fabio Stefan ; Hollmann, Claudia Beate ; Stonawski, Saskia ; Wurst, Catherina ; Fink, Julian ; Gorte, Erika ; Mandasari, Putri ; Domschke, Katharina ; Hommers, Leif ; Vanhove, Bernard ; Schumacher, Fabian ; Kleuser, Burkhard ; Seibel, Jürgen ; Rohr, Jan ; Buttmann, Mathias ; Menke, Andreas ; Schneider-Schaulies, Jürgen ; Beyersdorf, Niklas

Further information

• DOI: 10.1093/braincomms/fcab020
• URN: urn:nbn:de:bsz:25-freidok-2184246
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:55 PM CET