Autotaxin stimulates LPA2 receptor in macrophages and exacerbates dextran sulfate sodium-induced acute colitis.
Autotaxin stimulates LPA2 receptor in macrophages and exacerbates dextran sulfate sodium-induced acute colitis.
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Autotaxin 刺激巨噬细胞中的 LPA2 受体，加剧硫酸葡聚糖钠诱导的急性结肠炎。
DOI：
10.1007/s00109-020-01997-6
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Yu Qin
中科院分区：
文献类型：
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作者：
Wang Zi;Shi Wenjie;Tian Dean;Qin Hua;Vallance Bruce A;Yang Hyungjun;Yu Hong B;Yu Qin
自分泌运动因子（ATX）是一种分泌性酶，能水解溶血磷脂酰胆碱（LPC）生成溶血磷脂酸（LPA）和胆碱。ATX与多种慢性炎症性疾病有关，但其在炎症性肠病（IBD）发展中的作用知之甚少。在这里，我们研究了ATX如何导致结肠炎期间的肠道炎症。我们发现ATX表达水平在急性状态的溃疡性结肠炎（UC）患者的肠中以及在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠的肠中上调，这可能是由于包括巨噬细胞在内的炎性细胞的浸润增加。有趣的是，ATX活性的抑制导致炎性细胞因子的产生减少，以及结肠炎减弱。这些发现表明ATX可能显示出强烈的促炎特性。支持这一点的是，用重组小鼠ATX（rmATX）处理增加了小鼠巨噬细胞系RAW264.7和骨髓源性巨噬细胞（BMDM）中炎性细胞因子和酶的产生，而通过siRNA沉默ATX减少了LPS刺激的促炎因子的产生。值得注意的是，我们发现LPA 2（一种LPA受体）的水平在rmATX处理的RAW 264.7细胞和DSS处理的小鼠中显著上调。通过siRNA沉默RAW264.7细胞中flpa2的基因导致炎性细胞因子的产生减少。此外，腺病毒介导的递送flpa2短发夹RNA到DSS治疗的小鼠中改善结肠炎。总的来说，我们的研究表明ATX可能通过激活巨噬细胞中的LPA2受体而加重DSS诱导的结肠炎，并且是治疗IBD的有希望的靶点。关键信息结肠炎性结肠中ATX表达和分泌增加可能是由于包括巨噬细胞在内的炎性细胞浸润增加。重组ATX促进，但ATX沉默抑制，LPS刺激的RAW264.7细胞和BMDM中炎性细胞因子的产生。LPA 2介导ATX对巨噬细胞的促炎作用，抑制ATX和下调LPA 2可改善DSS诱导的结肠炎。
AbstractAutotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) and choline. ATX has been implicated in multiple chronic inflammatory diseases, but little is known about its role in the development of inflammatory bowel disease (IBD). Here, we investigated how ATX contributed to intestinal inflammation during colitis. We found that ATX expression levels were upregulated in the intestines of ulcerative colitis (UC) patients in acute state as well as in the intestines of dextran sulfate sodium (DSS)-induced colitis mice, which is likely due to increased infiltration of inflammatory cells including macrophages. Intriguingly, the inhibition of ATX activity led to reduced production of inflammatory cytokines, as well as attenuated colitis. These findings suggest that ATX may display strong pro-inflammatory properties. Supporting this, treatment with recombinant mouse ATX (rmATX) increased the production of inflammatory cytokines and enzymes in mouse macrophage cell line RAW264.7 and bone marrow-derived macrophages (BMDM), whereas silencing ATX by siRNA reduced LPS-stimulated production of pro-inflammatory factors. Notably, we found that the levels of LPA2 (an LPA receptor) were dramatically upregulated in rmATX-treated RAW264.7 cells and DSS-treated mice. Gene silencing oflpa2in RAW264.7 cells by siRNA led to reduced production of inflammatory cytokines. Moreover, adenovirus-mediated delivery oflpa2short hairpin RNA into DSS-treated mice ameliorated colitis. Collectively, our research suggests that ATX may exacerbate DSS-induced colitis by activating LPA2 receptor in macrophages and represent a promising target for the treatment of IBD.Key messagesIncreased ATX expression and secretion in colitic colons are likely due to increased infiltration of inflammatory cells including macrophages.Recombinant ATX promotes, but ATX silencing inhibits, the production of inflammatory cytokines in LPS-stimulated RAW264.7 cells and BMDM.•LPA2 mediates the pro-inflammatory effects of ATX on macrophages.Inhibition of ATX and downregulation of LPA2 ameliorate DSS-induced colitis.