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-Glut1fl/f /PBS, n=3; LysM-Cre-Glut1fl/fl /S. pneumoniae, n=3; LysM-Cre-Glut1fl/fl /Bleomycin, n=6; LysM-Cre-Glut1fl/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.

中文翻译：

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GLUT1依赖性糖酵解通过AIM2炎症小体激活调节纤维化的恶化


背景 特发性肺纤维化（IPF）是一种快速进展、致命的肺部疾病，影响老年人。 IPF 的有害自然史之一是 IPF 急性加重 (AE-IPF)，据报道细菌感染在其中发挥重要作用。然而，细菌感染调节纤维化反应的机制仍不清楚。目的 葡萄糖代谢改变与纤维化肺病的发病机制有关。我们之前已经证明，葡萄糖转运蛋白 1 (GLUT1) 依赖性糖酵解在小鼠纤维化模型中调节纤维形成。为了扩展这些发现，我们假设 GLUT1 依赖性糖酵解通过 AIM2 炎症小体激活调节细菌感染期间肺纤维化的急性恶化。结果在我们目前的研究中，我们使用肺炎链球菌（S.pneumoniae）感染的小鼠模型，研究了GLUT1在介导博来霉素诱导的纤维化期间急性加重的纤维化反应中的潜在作用。我们当前研究的结果表明，GLUT1 缺陷可改善肺炎链球菌介导的肺纤维化恶化（野生型 (WT)/磷酸盐缓冲盐水 (PBS)，n=3；WT/肺炎链球菌，n=3；WT/博莱霉素，n=5；WT/博莱霉素+S，n=7；LysM-Cre-Glut1fl/S，n=3； Cre-Glut1fl/fl/博来霉素，n=6；LysM-Cre-Glut1fl/fl/博来霉素+肺炎，n=9，p=0.041）。此外，AIM2 炎性体是一种多蛋白复合物，对于感知胞质细菌 DNA 作为危险信号至关重要，是 GLUT1 介导的纤维化的重要调节因子，AIM2 的遗传缺陷可减少肺炎链球菌感染后博莱霉素诱导的纤维化（WT/PBS， n=6；WT/博来霉素+S。 肺炎链球菌，n=15； Aim2−/−/PBS，n=6，Aim2−/−/博莱霉素+S。肺炎链球菌，n=11，p=0.034）。 GLUT1 缺陷会降低 AIM2 炎性体的表达和功能，并且 AIM2 缺陷小鼠在肺炎链球菌感染后显示肺纤维化大幅减少。结论 我们的结果表明，肺炎链球菌感染期间，GLUT1 依赖性糖酵解通过 AIM2 炎性体激活促进肺纤维化加剧。