Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China.
Department of Biochemistry and Molecular Biology, The University of Texas at Houston Medical School, The University of Texas, Houston, Texas, USA.
FASEB J. 2018 May;32(5):2855-2865. doi: 10.1096/fj.201600788RR. Epub 2018 Jan 17.
Sphingosine-1-phosphate (S1P) is a biolipid involved in chronic inflammation in several inflammatory disorders. Recent studies revealed that elevated S1P contributes to sickling in sickle cell disease (SCD), a devastating hemolytic, genetic disorder associated with severe chronic inflammation and tissue damage. We evaluated the effect of elevated S1P in chronic inflammation and tissue damage in SCD and underlying mechanisms. First, we demonstrated that interfering with S1P receptor signaling by FTY720, a U.S. Food and Drug Administration-approved drug, significantly reduced systemic, local inflammation and tissue damage without antisickling effects. These findings led us to discover that S1P receptor activation leads to substantial elevated local and systemic IL-6 levels in SCD mice. Genetic deletion of IL-6 in SCD mice significantly reduced local and systemic inflammation, tissue damage, and kidney dysfunction. At the cellular level, we determined that elevated IL-6 is a key cytokine functioning downstream of elevated S1P, which contributes to increased S1P receptor 1 ( S1pr1) gene expression in the macrophages of several tissues in SCD mice. Mechanistically, we revealed that S1P-S1PR1 signaling reciprocally up-regulated IL-6 gene expression in primary mouse macrophages in a JAK2-dependent manner. Altogether, we revealed that elevated S1P, coupled with macrophage S1PR1 reciprocally inducing IL-6 expression, is a key signaling network functioning as a malicious, positive, feed-forward loop to sustain inflammation and promote tissue damage in SCD. Our findings immediately highlight novel therapeutic possibilities.-Zhao, S., Adebiyi, M. G., Zhang, Y., Couturier, J. P., Fan, X., Zhang, H., Kellems, R. E., Lewis, D. E., Xia, Y. Sphingosine-1-phosphate receptor 1 mediates elevated IL-6 signaling to promote chronic inflammation and multitissue damage in sickle cell disease.
鞘氨醇-1-磷酸（S1P）是一种参与几种炎症性疾病慢性炎症的生物脂质。最近的研究表明，升高的 S1P 有助于镰状细胞病（SCD）中的镰状化，SCD 是一种破坏性的溶血性遗传疾病，与严重的慢性炎症和组织损伤有关。我们评估了升高的 S1P 在 SCD 中的慢性炎症和组织损伤中的作用及其潜在机制。首先，我们通过美国食品和药物管理局批准的 FTY720 干扰 S1P 受体信号，证明这显著减少了全身性、局部炎症和组织损伤，而没有抗镰状化作用。这些发现使我们发现 S1P 受体激活导致 SCD 小鼠中局部和全身性 IL-6 水平显著升高。SCD 小鼠中 IL-6 的基因缺失显著减少了局部和全身性炎症、组织损伤和肾功能障碍。在细胞水平上，我们确定升高的 IL-6 是一种关键细胞因子，作为升高的 S1P 的下游功能，导致 SCD 小鼠几种组织中的巨噬细胞中升高的 S1P 受体 1（S1pr1）基因表达增加。从机制上讲，我们揭示了 S1P-S1PR1 信号以 JAK2 依赖的方式在原代小鼠巨噬细胞中反向上调 IL-6 基因表达。总之，我们揭示了升高的 S1P 与巨噬细胞 S1PR1 相互诱导 IL-6 表达，是作为维持炎症和促进 SCD 中组织损伤的恶性、正反馈循环的关键信号网络。我们的发现立即突出了新的治疗可能性。-赵，S.，Adebiyi，M. G.，Zhang，Y.，Couturier，J. P.，Fan，X.，Zhang，H.，Kellems，R. E.，Lewis，D. E.，Xia，Y. 鞘氨醇-1-磷酸受体 1 介导升高的 IL-6 信号转导以促进镰状细胞病中的慢性炎症和多组织损伤。
