Genetic sphingosine kinase 1 deficiency significantly decreases synovial inflammation and joint erosions in murine TNF-alpha-induced arthritis.
Genetic sphingosine kinase 1 deficiency significantly decreases synovial inflammation and joint erosions in murine TNF-alpha-induced arthritis.
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DOI：
10.4049/jimmunol.1000644
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发表时间：
2010-08-15
期刊：
影响因子：
--
通讯作者：
Gilkeson GS
中科院分区：
文献类型：
--
作者：
Baker DA;Barth J;Chang R;Obeid LM;Gilkeson GS
SphK 1是一种将鞘氨醇转化为生物活性鞘氨醇-1-磷酸（S1 P）的酶。最近的体外数据表明SphK 1在TNFα介导的炎症中具有潜在作用。本研究的目的是确定SphK 1在TNFα介导的慢性炎症中的体内意义，并确定TNFα诱导的致病机制是SphK 1依赖的。为了实现这些目标，我们研究了SphK 1缺陷在TNFα诱导的慢性炎症性关节炎体内模型中的作用。在14-16周开始发生自发性炎性糜烂性关节炎的转基因hTNFα小鼠与C57 BL 6遗传背景的SphK 1敲除小鼠（SphK 1-/-）杂交。从4个月大开始，hTNF/SphK 1-/-小鼠具有显著较不严重的临床上明显的爪肿胀和畸形，较少的滑膜和关节周围炎症以及显著减少的骨侵蚀，如通过微CT图像定量测量的。从机制上讲，与hTNF/SphK 1 +/+同窝出生的小鼠相比，缺乏SphK 1的小鼠关节考克斯-2蛋白和滑膜Th 17细胞较少。踝关节滑膜组织的微阵列分析和实时RT-PCR表明，与hTNF/SphK 1 +/+小鼠相比，hTNF/SphK 1-/-小鼠具有增加的SOCS 3转录水平，这可能也有助于SphK 1缺陷小鼠的炎症减少。最后，与hTNF/SphK 1 +/+小鼠相比，hTNF/SphK 1-/-小鼠踝关节中检测到的成熟破骨细胞显著较少。这些数据表明SphK 1通过影响滑膜炎症和破骨细胞数量在hTNFα诱导的炎性关节炎中起关键作用。
SphK1 is an enzyme that converts sphingosine to bioactive sphingosine-1-phosphate (S1P). Recent in vitro data suggest a potential role of SphK1 in TNFα mediated inflammation. Our aims in this study were to determine the in vivo significance of SphK1 in TNFα mediated chronic inflammation and to define which pathogenic mechanisms induced by TNFα are SphK1 dependent. To pursue these aims, we studied the effect of SphK1 deficiency in an in vivo model of TNFα induced chronic inflammatory arthritis. Transgenic hTNFα mice, that develop spontaneous inflammatory erosive arthritis beginning at 14-16 weeks, were crossed with SphK1 null mice (SphK1-/-), on the C57BL6 genetic background. Beginning at 4 months of age, hTNF/SphK1-/- mice had significantly less severe clinically evident paw swelling and deformity, less synovial and periarticular inflammation and markedly decreased bone erosions as measured quantititatively through micro-CT images. Mechanistically, the mice lacking SphK1 had less articular COX-2 protein and fewer synovial Th17 cells than hTNF/SphK1+/+ littermates. Microarray analysis and real-time RT-PCR of the ankle synovial tissue demonstrated that hTNF/SphK1-/- mice had increased transcript levels of SOCS3 compared to hTNF/SphK1+/+ mice, likely also contributing to the decreased inflammation in the SphK1 deficient mice. Finally, significantly fewer mature osteoclasts were detected in the ankle joints of hTNF/SphK1-/- mice compared to hTNF/SphK1+/+ mice. These data indicate that SphK1 plays a key role in hTNFα induced inflammatory arthritis via impacting synovial inflammation and osteoclast number.
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