Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation
Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation
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神经酰胺合成酶5缺乏加重葡聚糖硫酸钠诱导的结肠炎和结肠癌变并损害T细胞活化
DOI：
10.3390/cancers12071753
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发表时间：
2020-07-01
期刊：
影响因子：
5.2
通讯作者：
Groesch, Sabine
中科院分区：
文献类型：
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作者：
El-Hindi, Khadija;Brachtendorf, Sebastian;Groesch, Sabine
神经酰胺合酶5是催化从鞘氨醇或二氢鞘氨醇产生神经酰胺的六种酶之一。神经酰胺是细胞膜的重要组成部分，并作为信号分子。先前已经表明，神经酰胺合酶6和2在几种动物模型中影响结肠炎，有时具有相反的作用。在这里，我们研究了右旋糖酐硫酸钠诱导的急性结肠炎和氧化偶氮甲烷/右旋糖酐硫酸钠诱导的结肠炎相关结肠癌的疾病过程中，与全球神经酰胺合成酶5敲除（CerS 5-ko）或与神经酰胺合成酶5敲除局限于结肠上皮（CerS 5 fl/fl VilCre）的小鼠。我们监测了这些小鼠的疾病发展并分析了结肠屏障功能以及免疫细胞状态。CerS 5-ko小鼠而不是CerS 5 fl/fl-VilCre小鼠更容易受到急性和慢性炎症的影响。然而，结肠上皮细胞的细胞屏障功能并没有受到神经酰胺合成酶5下调的干扰。相反，未经治疗的CerS 5-ko小鼠在脾脏、结肠和血液中显示出CD 3（+）免疫细胞数量减少，尤其是上皮内CD 8（+）T细胞，这在CerS 5 fl/fl Vil Cre小鼠中并不明显。CerS 5-ko小鼠结肠组织中T细胞数量的减少伴随着IL-1 β、IFN γ和IL-4表达的减少。体外研究表明，敲低T细胞中的神经酰胺合酶5会损害T细胞活化。总之，我们发现CerS 5-ko小鼠对葡聚糖硫酸钠诱导的结肠炎和氧化偶氮甲烷/葡聚糖硫酸钠诱导的结肠炎相关结肠癌更敏感。结肠上皮中T细胞数量的减少可能导致了这种效应，而在未经治疗的CerS 5-ko小鼠中已经是这种情况。
Ceramide synthase 5 is one of six enzymes that catalyze the production of ceramides from sphingosine or sphinganine. Ceramides are important components of cell membranes and act as signaling molecules. Previously it has been shown that ceramide synthase 6 and 2 influence colitis in several animal models with sometimes opposite effects. Here, we investigated the disease course of dextran sodium sulfate-induced acute colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer in mice with global ceramide synthase 5 knockout (CerS5-ko) or with ceramide synthase 5 knockout restricted to the colon epithelium (CerS5fl/fl VilCre). We monitored disease development and analyzed colon barrier function as well as the immune cell status in these mice. CerS5-ko mice but not CerS5fl/fl-VilCre mice were more susceptible to acute and chronic inflammation. However, the cell barrier function of colon epithelial cells was not disturbed by downregulation of ceramide synthase 5. Instead, untreated CerS5-ko mice displayed reduced numbers of CD3(+)immune cells in the spleen, colon, and blood, especially of intraepithelial CD8(+)T-cells, which was not obvious in CerS5fl/fl Vil Cre mice. Reduced T-cell number in colon tissue of CerS5-ko mice was accompanied by a reduced expression of IL-1 beta, IFN gamma, and IL-4. In vitro investigations revealed that knockdown of ceramide synthase 5 in T-cells impaired T-cell activation. In summary, we show that CerS5-ko mice were more susceptible to dextran sodium sulfate-induced colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer. A reduced number of T-cells in the colon epithelium that was already the case in untreated CerS5-ko mice might have contributed to this effect.