| First Author | Cho SJ | Year | 2020 |
| Journal | Thorax | Volume | 75 |
| Issue | 3 | Pages | 227-236 |
| PubMed ID | 31822523 | Mgi Jnum | J:315641 |
| Mgi Id | MGI:6829460 | Doi | 10.1136/thoraxjnl-2019-213571 |
| Citation | Cho SJ, et al. (2020) GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation. Thorax 75(3):227-236 |
| abstractText | 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. |
