The Siponimod (Mayzent) is a newly developed drug, similar to Fingolimod (FTY720) but with fewer side effects, approved by the Food and Drug Administration for the treatment of multiple sclerosis (MS). The therapeutic effect of siponimod and FTY720 in MS relies on their inhibitory effect on the sphingosine 1-phosphate (S1P) signaling. These drugs bind to the S1P receptors and block the CCL2 chemokine pathway that is responsible for the exit of the immune cells from the lymphoid organs, and circulation, thus preventing immune cell-dependent injury to the nervous system. We recently found that FTY720 beside its effect on the S1P pathway also blocks the RhoA pathway, which is involved in the actin cytoskeleton-related function of macrophages, such as expression/recycling of fractalkine (CX3CL1) receptors (CX3CR1), which direct macrophages to the transplanted organs during the development of the long-term (chronic) rejection. Here we tested the effects of siponimod on the RhoA pathway and the expression of the S1P1 and CX3CR1 receptors in mouse RAW 264.7 macrophages. We found that siponimod downregulates the expression of RhoA protein and decreases the cell surface expression of S1P1 and CX3CR1 receptors. This newly discovered crosstalk between S1P and RhoA/CX3CR1 pathways may help in the development of novel anti-chronic rejection therapies in clinical transplantation.

Siponimod（Mayzent）是一种新开发的药物，与Fingolimod（FTY720）相似，但副作用较小，已获得美国食品药品监督管理局（FDA）批准用于治疗多发性硬化症（MS）。西普尼莫德和FTY720在MS中的治疗效果取决于它们对1-磷酸鞘氨醇（S1P）信号传导的抑制作用。这些药物与S1P受体结合并阻断CCL2趋化因子途径，该途径负责免疫细胞从淋巴器官的排出和循环，从而防止免疫细胞依赖性损伤神经系统。我们最近发现FTY720除了对S1P途径有影响外，还阻断了RhoA途径，RhoA途径与巨噬细胞的肌动蛋白细胞骨架相关功能有关，例如分链蛋白（CX3CL1）受体（CX3CR1）的表达/回收，在长期（慢性）排斥反应的发展过程中将巨噬细胞引导至移植的器官。在这里，我们测试了西普尼莫德对RhoA途径的影响以及小鼠RAW 264.7巨噬细胞中S1P1和CX3CR1受体的表达。我们发现siponimod下调RhoA蛋白的表达并降低S1P1和CX3CR1受体的细胞表面表达。S1P和RhoA / CX3CR1通路之间的这种新发现的串扰可能有助于临床移植中新型抗慢性排斥疗法的发展。我们发现siponimod下调RhoA蛋白的表达并降低S1P1和CX3CR1受体的细胞表面表达。S1P和RhoA / CX3CR1通路之间的这种新发现的串扰可能有助于临床移植中新型抗慢性排斥疗法的发展。我们发现西普尼莫德下调RhoA蛋白的表达并降低S1P1和CX3CR1受体的细胞表面表达。S1P和RhoA / CX3CR1通路之间这种新发现的串扰可能有助于临床移植中新型抗慢性排斥疗法的发展。