GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation. Issue 3 (10th December 2019)

• Record Type: Journal Article
• Authors: Cho, Soo Jung; Moon, Jong-Seok; Nikahira, Kiichi; Yun, Ha Seon; Harris, Rebecca; Hong, Kyung Sook; Huang, Huarong; Choi, Augustine M K; Stout-Delgado, Heather
• Is Part Of: Thorax. Volume 75:Issue 3(2020)
• Page Start: 227
• Page End: 236
• Publication Date: 2019-12-10
• Subjects: idiopathic pulmonary fibrosis -- pneumonia -- interstitial fibrosis; Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thoraxjnl-2019-213571
• Languages: English
• ISSNs: 0040-6376

Abstract

Abstract : 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.