Wang K, Xu R, Snider A J, Schrandt J, Li Y, Bialkowska A B, Li M, Zhou J, Hannun Y A, Obeid L M, Yang V W, Mao C
Department of Medicine, State University of New York at Stony Brook University, Stony Brook, NY, USA.
Stony Brook Cancer Center, Stony Brook, NY, USA.
Cell Death Dis. 2016 Mar 3;7(3):e2124. doi: 10.1038/cddis.2016.36.
Increasing studies suggest that ceramides differing in acyl chain length and/or degree of unsaturation have distinct roles in mediating biological responses. However, still much remains unclear about regulation and role of distinct ceramide species in the immune response. Here, we demonstrate that alkaline ceramidase 3 (Acer3) mediates the immune response by regulating the levels of C18:1-ceramide in cells of the innate immune system and that Acer3 deficiency aggravates colitis in a murine model by augmenting the expression of pro-inflammatory cytokines in myeloid and colonic epithelial cells (CECs). According to the NCBI Gene Expression Omnibus (GEO) database, ACER3 is downregulated in immune cells in response to lipopolysaccharides (LPS), a potent inducer of the innate immune response. Consistent with these data, we demonstrated that LPS downregulated both Acer3 mRNA levels and its enzymatic activity while elevating C(18:1)-ceramide, a substrate of Acer3, in murine immune cells or CECs. Knocking out Acer3 enhanced the elevation of C(18:1)-ceramide and the expression of pro-inflammatory cytokines in immune cells and CECs in response to LPS challenge. Similar to Acer3 knockout, treatment with C(18:1)-ceramide, but not C18:0-ceramide, potentiated LPS-induced expression of pro-inflammatory cytokines in immune cells. In the mouse model of dextran sulfate sodium-induced colitis, Acer3 deficiency augmented colitis-associated elevation of colonic C(18:1)-ceramide and pro-inflammatory cytokines. Acer3 deficiency aggravated diarrhea, rectal bleeding, weight loss and mortality. Pathological analyses revealed that Acer3 deficiency augmented colonic shortening, immune cell infiltration, colonic epithelial damage and systemic inflammation. Acer3 deficiency also aggravated colonic dysplasia in a mouse model of colitis-associated colorectal cancer. Taken together, these results suggest that Acer3 has an important anti-inflammatory role by suppressing cellular or tissue C(18:1)-ceramide, a potent pro-inflammatory bioactive lipid and that dysregulation of ACER3 and C(18:1)-ceramide may contribute to the pathogenesis of inflammatory diseases including cancer.
越来越多的研究表明，酰基链长度和/或不饱和度不同的神经酰胺在介导生物学反应中具有不同的作用。然而，关于不同种类神经酰胺在免疫反应中的调节和作用仍有许多不清楚的地方。在此，我们证明碱性神经酰胺酶3（Acer3）通过调节先天性免疫系统细胞中C18:1-神经酰胺的水平来介导免疫反应，并且Acer3缺陷通过增强骨髓和结肠上皮细胞（CEC）中促炎细胞因子的表达而加重小鼠模型中的结肠炎。根据NCBI基因表达综合数据库（GEO），ACER3在免疫细胞中因脂多糖（LPS）（一种先天性免疫反应的强效诱导剂）而下调。与这些数据一致，我们证明LPS在小鼠免疫细胞或CEC中下调Acer3 mRNA水平及其酶活性，同时升高Acer3的底物C(18:1)-神经酰胺。敲除Acer3增强了免疫细胞和CEC中C(18:1)-神经酰胺的升高以及对LPS刺激的促炎细胞因子的表达。与敲除Acer3类似，用C(18:1)-神经酰胺而非C18:0-神经酰胺处理可增强免疫细胞中LPS诱导的促炎细胞因子的表达。在葡聚糖硫酸钠诱导的结肠炎小鼠模型中，Acer3缺陷加剧了结肠炎相关的结肠C(18:1)-神经酰胺和促炎细胞因子的升高。Acer3缺陷加重了腹泻、直肠出血、体重减轻和死亡率。病理分析显示，Acer3缺陷加剧了结肠缩短、免疫细胞浸润、结肠上皮损伤和全身炎症。Acer3缺陷在结肠炎相关结直肠癌小鼠模型中也加重了结肠发育异常。综上所述，这些结果表明Acer3通过抑制细胞或组织中的C(18:1)-神经酰胺（一种强效促炎生物活性脂质）具有重要的抗炎作用，并且ACER3和C(18:1)-神经酰胺的失调可能导致包括癌症在内的炎症性疾病的发病机制。
