Wiese Teresa, Dennstädt Fabio, Hollmann Claudia, 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
Institute for Virology and Immunobiology, University of Würzburg, Würzburg 97078, Germany.
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg 97080, Germany.
Brain Commun. 2021 Mar 5;3(2):fcab020. doi: 10.1093/braincomms/fcab020. eCollection 2021.
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 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 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 and .
酸性鞘磷脂酶基因缺陷或其药理学抑制已被证明可增加小鼠CD4 T细胞中Foxp3调节性T细胞的频率。我们现在研究了对催化鞘磷脂裂解为神经酰胺和磷酸胆碱的酸性鞘磷脂酶进行药理学靶向是否也能调控人类CD4 Foxp3调节性T细胞的相对频率。使用如舍曲林等抗抑郁药对酸性鞘磷脂酶进行药理学抑制，而非对酸性鞘磷脂酶活性无抑制作用的如西酞普兰等抗抑郁药，可增加人类CD4 T细胞中Foxp3调节性T细胞的频率。在一项针对重度抑郁症患者的观察性前瞻性临床研究中，我们观察到，与对酸性鞘磷脂酶无抑制或抑制作用较弱的抗抑郁药相比，抑制酸性鞘磷脂酶的抗抑郁药在外周血中诱导CD4 Foxp3调节性T细胞频率出现更强的相对增加。对于CD45RA CD25效应性CD4 Foxp3调节性T细胞尤其如此。从机制上讲，我们的数据表明，酸性鞘磷脂酶抑制对CD4 Foxp3调节性T细胞的积极作用需要CD28共刺激，这表明增强的CD28共刺激是观察到的人类CD4 T细胞中Foxp3调节性T细胞频率增加的驱动因素。总之，在患者中广泛诱导的酸性鞘磷脂酶活性药理学抑制导致人类CD4 T细胞中Foxp3调节性T细胞频率增加。
