Le Daré Brendan, Victoni Tatiana, Bodin Aude, Vlach Manuel, Vene Elise, Loyer Pascal, Lagente Vincent, Gicquel Thomas
INSERM, INRA, CHU Rennes, Institut NuMeCan (Nutrition, Metabolism and Cancer), Univ Rennes, F-35000, Rennes, France.
Pharmacy Service, Pontchaillou University Hospital, F-35000, Rennes, France.
Fundam Clin Pharmacol. 2019 Feb;33(1):63-74. doi: 10.1111/fcp.12433. Epub 2018 Dec 3.
Alcohol consumption is considered to be the third leading cause of death in the United States. In addition to its direct toxicity, ethanol has two contrasting effects on the immune system: the nucleotide oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is inhibited by acute ethanol exposure but activated by chronic ethanol exposure. Purinergic receptors (especially the P2X7 receptor) are able to activate the NLRP3 inflammasome and are involved in many ethanol-related diseases (such as gout, pulmonary fibrosis, alcoholic steatohepatitis, and certain cancers). We hypothesized that ethanol regulates purinergic receptors and thus modulates the NLRP3 inflammasome's activity. In experiments with monocyte-derived macrophages, we found that interleukin (IL)-1β secretion was inhibited after 7 h of exposure (but not 48 h of exposure) to ethanol. The disappearance of ethanol's inhibitory effect on IL-1β secretion after 48 h was not mediated by the upregulated production of IL-1β, IL-1α, IL-6 or the inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase 1. P2X7R expression was upregulated by ethanol, whereas expression of the P2X4 and P2X1 receptors was not. Taken as a whole, our results suggest that ethanol induces NLRP3 inflammasome activation by upregulating the P2X7 receptor. This observation might have revealed a new mechanism for inflammation in ethanol-related diseases.
在美国，饮酒被认为是第三大死因。除了直接毒性外，乙醇对免疫系统有两种相反的作用：急性乙醇暴露会抑制含核苷酸寡聚化结构域样受体吡啉结构域3（NLRP3）炎性小体，但慢性乙醇暴露会激活它。嘌呤能受体（尤其是P2X7受体）能够激活NLRP3炎性小体，并参与许多与乙醇相关的疾病（如痛风、肺纤维化、酒精性脂肪性肝炎和某些癌症）。我们推测乙醇调节嘌呤能受体，从而调节NLRP3炎性小体的活性。在单核细胞衍生巨噬细胞的实验中，我们发现暴露于乙醇7小时后（而非48小时后）白细胞介素（IL）-1β分泌受到抑制。48小时后乙醇对IL-1β分泌的抑制作用消失，这不是由IL-1β、IL-1α、IL-6或炎性小体成分NLRP3、含半胱天冬酶募集结构域的凋亡相关斑点样蛋白和半胱天冬酶1的上调产生介导的。乙醇上调了P2X7R的表达，而P2X4和P2X1受体的表达没有上调。总体而言，我们的结果表明乙醇通过上调P2X7受体诱导NLRP3炎性小体激活。这一观察结果可能揭示了乙醇相关疾病炎症的一种新机制。
