Departments of Comparative Medicine, Medical University of South Carolina, Charleston, SC, USA.
Pharmacology, Medical University of South Carolina, Charleston, SC, USA.
Sci Rep. 2018 Jan 26;8(1):1627. doi: 10.1038/s41598-018-20102-z.
Colitis, an inflammatory disease of the digestive tract, is increasing in incidence and prevalence. Intestinal inflammation can occur as a consequence of dysfunctions in sphingolipid metabolism. In this study we used ceramide synthase 6 (CerS6) deficient mice, which have a reduced ability to generate long chain C-ceramide, to investigate the role of this enzyme in dextran sodium salt (DSS)-induced colitis. While CerS6-deficient mice are protected from T cell mediated colitis, in the T cell independent DSS model lack of CerS6 resulted in a more rapid onset of disease symptoms. CerS6-deficient mice maintained low levels of C-ceramide after DSS treatment, but the inflammatory lipid sphingosine-1-phosphate was significantly increased in colon tissue. In the absence of CerS6, DSS induced more severe pathology in the colon including enhanced neutrophil infiltration. In vivo analysis of myeloperoxidase activity, an enzyme released from neutrophils, was approximately 2.5-fold higher in CerS6-deficient mice compared to wild type. Differences in intestinal permeability did not account for the increase in neutrophils. Our study suggests that lack of CerS6 expression differentially impacts the development of colitis, depending on the model used.
结肠炎，一种消化道炎症性疾病，其发病率和患病率都在上升。肠道炎症可能是鞘脂代谢功能障碍的结果。在这项研究中，我们使用了神经酰胺合酶 6（CerS6）缺乏的小鼠，这些小鼠生成长链 C 神经酰胺的能力降低，以此来研究该酶在葡聚糖硫酸钠（DSS）诱导的结肠炎中的作用。虽然 CerS6 缺乏的小鼠可以预防 T 细胞介导的结肠炎，但在 T 细胞非依赖性 DSS 模型中，缺乏 CerS6 会导致疾病症状更快出现。CerS6 缺乏的小鼠在 DSS 处理后仍保持低水平的 C 神经酰胺，但在结肠组织中，炎症脂质 1-磷酸鞘氨醇的含量显著增加。在缺乏 CerS6 的情况下，DSS 会导致结肠更严重的病理变化，包括中性粒细胞浸润增加。体内分析髓过氧化物酶活性（一种从中性粒细胞中释放的酶），CerS6 缺乏的小鼠比野生型小鼠高约 2.5 倍。中性粒细胞增加并不是由于肠道通透性的差异造成的。我们的研究表明，CerS6 表达的缺乏会根据所使用的模型而对结肠炎的发展产生不同的影响。
