GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation
GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation
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DOI：
10.1136/thoraxjnl-2019-213571
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发表时间：
2020-03-01
期刊：
影响因子：
10
通讯作者：
Stout-Delgado, Heather
中科院分区：
文献类型：
--
作者：
Cho, Soo Jung;Moon, Jong-Seok;Stout-Delgado, Heather
背景特发性肺纤维化(IPF)是一种进展迅速、影响老年人的致命性肺部疾病。IPF的有害自然病史之一是IPF的急性加重(AE-IPF)，据报道细菌感染在其中起重要作用。然而，细菌感染调节纤维化反应的机制尚不清楚。目的糖代谢改变与纤维化肺疾病的发病机制有关。我们先前已经证明，葡萄糖转运蛋白1(GLUT1)依赖的糖酵解在小鼠纤维化模型中调节纤维化的形成。为了扩展这些发现，我们假设GLUT1依赖的糖酵解通过激活AIM2炎症小体来调节细菌感染期间肺纤维化的急性加重。结果在我们目前的研究中，使用肺炎链球菌(肺炎链球菌)感染的小鼠模型，我们研究了GLUT1在博莱霉素诱导的纤维化过程中介导急性加重的纤维化反应中的潜在作用。我们目前的研究结果表明，GLUT1缺乏改善了肺炎链球菌介导的肺纤维化加重(野生型(WT)/磷酸盐缓冲盐水(PBS)，n=3；野生型/肺炎链球菌，n=3；WT/博莱霉素，n=5；WT/博莱霉素+肺炎链球菌，n=7；LysM-Cre-Glut1(f1/f)/PBS，n=3；LysM-Cre-Glt1(fl/fl)/肺炎链球菌，n=3；LysM-CRE-Glt1(fl/fl)/博莱霉素，n=6；LysM-CRE-Glt1(fl/fl)/博莱霉素，n=0.041)。此外，AIM2炎症体是GLUT1介导的纤维化的重要调节因子，并且AIM2基因缺陷减少了博莱霉素诱导的肺炎链球菌感染后的纤维化(WT/PBS，n=6；WT/博莱霉素+肺炎链球菌，n=15；AIM2-/-/PBS，n=6，AIM2-/-/PBS，n=6，AIM2(-/-)/博莱霉素+肺炎链球菌，n=0.034)。结论Glut1依赖的糖酵解通过激活AIM2炎症体促进肺炎链球菌感染时肺纤维化的加重。
Background Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive, fatal lung disease that affects older adults. One of the detrimental natural histories of IPF is acute exacerbation of IPF (AE-IPF), of which bacterial infection is reported to play an important role. However, the mechanism by which bacterial infection modulates the fibrotic response remains unclear.Objectives Altered glucose metabolism has been implicated in the pathogenesis of fibrotic lung diseases. We have previously demonstrated that glucose transporter 1 (GLUT1)-dependent glycolysis regulates fibrogenesis in a murine fibrosis model. To expand on these findings, we hypothesised that GLUT1-dependent glycolysis regulates acute exacerbation of lung fibrogenesis during bacterial infection via AIM2 inflammasome activation.Results In our current study, using a murine model of Streptococcus pneumoniae (S. pneumoniae) infection, we investigated the potential role of GLUT1 on mediating fibrotic responses to an acute exacerbation during bleomycin-induced fibrosis. The results of our current study illustrate that GLUT1 deficiency ameliorates S. pneumoniae-mediated exacerbation of lung fibrosis (wild type (WT)/phosphate buffered saline (PBS), n=3; WT/S. pneumoniae, n=3; WT/Bleomycin, n=5; WT/Bleomycin+S. pneumoniae, n=7; LysM-Cre-Glut1(fl/f)/PBS, n=3; LysM-Cre-Glut1(fl/fl)/S. pneumoniae, n=3; LysM-Cre-Glut1(fl/fl)/Bleomycin, n=6; LysM-Cre-Glut1(fl/fl)/Bleomycin+S. pneumoniae, n=9, p=0.041). Further, the AIM2 inflammasome, a multiprotein complex essential for sensing cytosolic bacterial DNA as a danger signal, is an important regulator of this GLUT1-mediated fibrosis and genetic deficiency of AIM2 reduced bleomycin-induced fibrosis after S. pneumoniae infection (WT/PBS, n=6; WT/Bleomycin+S. pneumoniae, n=15; Aim2-/-/PBS, n=6, Aim2(-/-)/Bleomycin+S. pneumoniae, n=11, p=0.034). GLUT1 deficiency reduced expression and function of the AIM2 inflammasome, and AIM2-deficient mice showed substantial reduction of lung fibrosis after S. pneumoniae infection.Conclusion Our results demonstrate that GLUT1-dependent glycolysis promotes exacerbation of lung fibrogenesis during S. pneumoniae infection via AIM2 inflammasome activation.