TY - JOUR
T1 - GLUT1-dependent glycolysis regulates exacerbation of fibrosis via AIM2 inflammasome activation
AU - Cho, Soo Jung
AU - Moon, Jong Seok
AU - Nikahira, Kiichi
AU - Yun, Ha Seon
AU - Harris, Rebecca
AU - Hong, Kyung Sook
AU - Huang, Huarong
AU - Choi, Augustine M.K.
AU - Stout-Delgado, Heather
N1 - Funding Information:
This work was supported by the K08HL138285 (SJC), American Lung Association Biomedical Grant (SJC), R01AG052530 (HWS) and R01AG056699 (HWS).
Funding Information:
Funding This work was supported by the K08hl138285 (sJc), american lung association Biomedical grant (sJc), r01ag052530 (hWs) and r01ag056699 (hWs).
Publisher Copyright:
© © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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.
KW - idiopathic pulmonary fibrosis
KW - interstitial fibrosis
KW - pneumonia
KW - Inflammasomes/genetics
KW - Humans
KW - Gene Knockout Techniques
KW - Glucose Transporter Type 1/genetics
KW - Disease Progression
KW - Animals
KW - Bleomycin
KW - Pneumococcal Infections/complications
KW - Fibrosis
KW - Glycolysis
KW - Lung/pathology
KW - Mice
KW - Idiopathic Pulmonary Fibrosis/chemically induced
KW - Disease Models, Animal
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U2 - 10.1136/thoraxjnl-2019-213571
DO - 10.1136/thoraxjnl-2019-213571
M3 - Article
C2 - 31822523
AN - SCOPUS:85076707621
SN - 0040-6376
VL - 75
SP - 227
EP - 236
JO - Thorax
JF - Thorax
IS - 3
ER -