Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice
Alcohol-induced IL-17A production in Paneth cells amplifies endoplasmic reticulum stress, apoptosis, and inflammasome-IL-18 activation in the proximal small intestine in mice
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DOI：
10.1038/s41385-019-0170-4
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发表时间：
2019-07-01
影响因子：
8
通讯作者：
Szabo, G.
中科院分区：
文献类型：
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作者：
Gyongyosi, B.;Cho, Y.;Szabo, G.
肠道微生物易位导致酒精性肝炎。利用酒精性肝炎的小鼠模型，我们研究了慢性酒精加酗酒的影响，发现近端小肠(PSI)中Paneth细胞和IL-17A的丰富。酒精通过C/EBP同源蛋白(CHOP)上调所指示的内质网(ER)应激，增加IL-17A的产生，并通过Bax、Bim、caspase-3和caspase-8增加促凋亡信号；这在体外和体内的分离隐窝中被ER应激抑制剂4-PBA所阻止。从机制上讲，IL-17可增强酒精诱导的内质网应激。在体内，在酒精处理的小鼠中注射IL-17A阻断抗体可以减轻内质网应激诱导的细胞凋亡和IL-18诱导，并防止酒精引起的PSI和内毒素转位到肝脏的紧密连接的损害。急性-慢性酒精可导致PSI内炎症小体激活、caspase-1裂解和IL-18产生。体内应用抗生素或4-PBA可阻止CHOP上调和炎性小体激活。我们的数据表明，酒精通过增加Paneth细胞数量和IL-17A释放来上调先天免疫机制，有助于PSI中的细胞凋亡放大、炎性小体激活和肠道渗漏。酗酒诱导的PSI中的Paneth细胞扩张、内质网应激和炎症体激活是由肠道微生物群调节的。
Gut microbial translocation contributes to alcoholic hepatitis. Using a mouse model of alcoholic hepatitis, we investigated the effects of chronic alcohol plus binge and found increased abundance of Paneth cells and IL-17A in the proximal small intestine (PSI). Alcohol increased IL-17A production and pro-apoptotic signaling evidenced by Bax, Bim, caspase-3, and caspase-8 increases via endoplasmic reticulum (ER) stress indicated by C/EBP homologous protein (CHOP) upregulation; this was prevented by the ER stress inhibitor, 4-PBA, in isolated crypts in vitro and in vivo. Mechanistically, IL-17 augmented alcohol-induced ER stress in isolated crypts. In vivo IL-17A blocking antibody administration in alcohol-treated mice attenuated ER stress-mediated apoptosis and IL-18 induction and prevented alcohol-induced impairment of tight junctions in the PSI and LPS translocation to the liver. Acute-on-chronic alcohol resulted in inflammasome activation, caspase-1 cleavage, and IL-18 production in the PSI. In vivo treatment with antibiotics or 4-PBA prevented CHOP upregulation and inflammasome activation. Our data suggest that alcohol upregulates innate immune mechanisms by increasing Paneth cell numbers and IL-17A release contributing to apoptosis amplification, inflammasome activation, and gut leakiness in the PSI. Binge alcohol-induced Paneth cell expansion, ER stress, and inflammasome activation in the PSI are modulated by the gut microbiome.