Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system.
Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system.
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DOI：
10.1038/cddis.2016.36
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发表时间：
2016-03-03
影响因子：
9
通讯作者：
Mao C
中科院分区：
文献类型：
--
作者：
Wang K;Xu R;Snider AJ;Schrandt J;Li Y;Bialkowska AB;Li M;Zhou J;Hannun YA;Obeid LM;Yang VW;Mao C
越来越多的研究表明，酰基链长和/或不饱和度不同的神经酰胺在介导生物反应方面具有不同的作用。然而，关于不同神经酰胺种类在免疫反应中的调节和作用仍有许多不清楚的地方。在这里，我们证明了碱性神经酰胺酶3(Acer3)通过调节天然免疫系统细胞中C18：1-神经酰胺的水平来介导免疫反应，并且Acer3缺乏通过增加髓系和结肠上皮细胞(CECs)中促炎症细胞因子的表达来加重结肠炎。根据NCBI基因表达总览(GEO)数据库，ACER3在免疫细胞中下调是对内毒素(LPS)的反应，脂多糖是天然免疫反应的有效诱导剂。与这些数据一致，我们发现，在小鼠免疫细胞或CECs中，内毒素下调Acer3的mRNA水平及其酶活性，而上调Acer3的底物C18：1-神经酰胺。敲除Acer3基因后，免疫细胞和CECs中C18：1-神经酰胺的升高和促炎细胞因子的表达增强。与Acer3基因敲除相似，C18：1-神经酰胺处理，而不是C18：0-神经酰胺处理，增强了内毒素诱导的免疫细胞中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缺乏增加了结肠炎相关的C18：1神经酰胺和促炎细胞因子的升高。Acer3缺乏可加重腹泻、直肠出血、体重减轻和死亡率。病理分析显示，Acer3缺乏可增加结肠缩短、免疫细胞浸润、结肠上皮损伤和全身炎症。在结肠炎相关的结直肠癌小鼠模型中，Acer3缺乏也加剧了结肠发育不良。综上所述，这些结果表明，Acer3通过抑制细胞或组织中的C18：1-神经酰胺具有重要的抗炎作用，C18：1-神经酰胺是一种有效的促炎生物活性脂质，ACER3和C18：1-神经酰胺的失调可能参与了包括癌症在内的炎症性疾病的发病机制。
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 C18:1-ceramide, a substrate of Acer3, in murine immune cells or CECs. Knocking out Acer3 enhanced the elevation of C18:1-ceramide and the expression of pro-inflammatory cytokines in immune cells and CECs in response to LPS challenge. Similar to Acer3 knockout, treatment with C18:1-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 C18:1-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 C18:1-ceramide, a potent pro-inflammatory bioactive lipid and that dysregulation of ACER3 and C18:1-ceramide may contribute to the pathogenesis of inflammatory diseases including cancer.