Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India.
Manipal Academy of Higher Education (MAHE), Manipal, India.
FASEB J. 2019 Jun;33(6):7061-7071. doi: 10.1096/fj.201802535R. Epub 2019 Mar 6.
Systemic lupus erythematosus is an autoimmune disease characterized by overproduction of type 1 IFN that causes multiple organ dysfunctions. Plasmacytoid dendritic cells (pDCs) that secrete large amounts of IFN have recently been implicated in the initiation of the disease in preclinical mouse models. Sphingosine-1-phosphate, a bioactive sphingolipid metabolite, is produced by 2 highly conserved isoenzymes, sphingosine kinase (SphK) 1 and SphK2, and regulates diverse processes important for immune responses and autoimmunity. However, not much is known about the role of SphK2 in autoimmune disorders. In this work, we examined the role of SphK2 in pDC development and activation and in the pristane-induced lupus model in mice that mimics the hallmarks of the human disease. Increases in pDC-specific markers were observed in peripheral blood of SphK2 knockout mice. In agreement, the absence of SphK2 increased the differentiation of FMS-like tyrosine kinase 3 ligand dendritic cells as well as expression of endosomal TLRs, TLR7 and TLR9, that modulate production of IFN. Surprisingly, however, SphK2 deficiency did not affect the initiation or progression of pristane-induced lupus. Moreover, although absence of SphK2 increased pDC frequency in pristane-induced lupus, there were no major changes in their activation status. Additionally, SphK2 expression was unaltered in lupus patients. Taken together, our results suggest that SphK2 may play a role in dendritic cell development. Yet, because its deletion had no effect on the clinical lupus parameters in this preclinical model, inhibitors of SphK2 might not be useful for treatment of this devastating disease.-Mohammed, S., Vineetha, N. S., James, S., Aparna, J. S., Lankadasari, M. B., Allegood, J. C., Li, Q.-Z., Spiegel, S., Harikumar, K. B. Examination of the role of sphingosine kinase 2 in a murine model of systemic lupus erythematosus.
系统性红斑狼疮是一种自身免疫性疾病，其特征是 1 型 IFN 过度产生，导致多器官功能障碍。浆细胞样树突状细胞（pDC）大量分泌 IFN，最近被认为在临床前小鼠模型中引发了疾病的发生。鞘氨醇-1-磷酸是一种生物活性鞘脂代谢物，由 2 种高度保守的同工酶——鞘氨醇激酶（SphK）1 和 SphK2 产生，调节免疫反应和自身免疫中多种重要过程。然而，对于 SphK2 在自身免疫性疾病中的作用知之甚少。在这项工作中，我们研究了 SphK2 在 pDC 发育和激活以及在模拟人类疾病特征的 pristane 诱导狼疮模型中的作用。在 SphK2 敲除小鼠的外周血中观察到 pDC 特异性标记物增加。同样，SphK2 的缺失增加了 FMS 样酪氨酸激酶 3 配体树突状细胞的分化以及内体 TLRs（TLR7 和 TLR9）的表达，这些 TLRs 调节 IFN 的产生。然而，令人惊讶的是，SphK2 缺乏并不影响 pristane 诱导的狼疮的起始或进展。此外，尽管 SphK2 的缺失增加了 pristane 诱导的狼疮中的 pDC 频率，但它们的激活状态没有发生重大变化。此外，SphK2 在狼疮患者中的表达没有改变。总之，我们的结果表明 SphK2 可能在树突状细胞发育中发挥作用。然而，由于其缺失对这种临床前模型中的狼疮临床参数没有影响，因此 SphK2 的抑制剂可能对治疗这种毁灭性疾病没有用处。-Mohammed，S.，Vineetha，N. S.，James，S.，Aparna，J. S.，Lankadasari，M. B.，Allegood，J. C.，Li，Q.-Z.，Spiegel，S.，Harikumar，K. B. 检查 SphK2 在系统性红斑狼疮小鼠模型中的作用。
