GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation.

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 () 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 -mediated exacerbation of lung fibrosis (wild type (WT)/phosphate buffered saline (PBS), n=3; WT/, n=3; WT/Bleomycin, n=5 ; WT/Bleomycin+, n=7; /PBS, n=3; /, n=3; /Bleomycin, n=6; /Bleomycin+, 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 infection (WT/PBS, n=6; WT/Bleomycin+, n=15; Aim2/PBS, n=6, Aim2/Bleomycin+, 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 infection.

Conclusion: Our results demonstrate that GLUT1-dependent glycolysis promotes exacerbation of lung fibrogenesis during infection via AIM2 inflammasome activation.