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

Abstract

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. 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. In our current study, using a murine model of <i>Streptococcus pneumoniae</i> (<i>S. pneumoniae</i>) 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 <i>S. pneumoniae</i>-mediated exacerbation of lung fibrosis (wild type (WT)/phosphate buffered saline (PBS), n=3; WT/<i>S. pneumoniae</i>, n=3; WT/Bleomycin, n=5 ; WT/Bleomycin+<i>S. pneumoniae</i>, n=7; <i>LysM-Cre-Glut1^fl/f</i> /PBS, n=3; <i>LysM-Cre-Glut1^fl/fl</i> /<i>S. pneumoniae</i>, n=3; <i>LysM-Cre-Glut1^fl/fl</i> /Bleomycin, n=6; <i>LysM-Cre-Glut1^fl/fl</i> /Bleomycin+<i>S. pneumoniae</i>, 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 <i>S. pneumoniae</i> infection (WT/PBS, n=6; WT/Bleomycin+<i>S. pneumoniae</i>, n=15; Aim2^-/-/PBS, n=6, Aim2^-/-/Bleomycin+<i>S. pneumoniae</i>, 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 <i>S. pneumoniae</i> infection. Our results demonstrate that GLUT1-dependent glycolysis promotes exacerbation of lung fibrogenesis during <i>S. pneumoniae</i> infection via AIM2 inflammasome activation.