TY - JOUR
T1 - Down-regulation of guanylate binding protein 1 causes mitochondrial dysfunction and cellular senescence in macrophages
AU - Qiu, Xiaoxue
AU - Guo, Hong
AU - Yang, Junshu
AU - Ji, Yinduo
AU - Wu, Chia Shan
AU - Chen, Xiaoli
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Macrophage polarization is tightly associated with its metabolic reprograming and immune dysfunction. However, the intracellular molecules/pathways that connect these alterations in inflammatory macrophages remain largely unidentified. Herein, we explored the role of guanylate binding protein 1 (Gbp1), an intracellular anti-microbial protein, in regulating polarization, metabolic reprogramming, and cellular aging of macrophages. We showed that Gbp1 expression in inguinal white adipose tissue is significantly decreased in high-fat diet -fed and aged mice. Gbp1 expression is significantly induced by IFNγ and LPS in macrophages but not adipocytes. Downregulation of Gbp1 expression causes macrophage polarization towards a pro-inflammatory phenotype. Gbp1 knockdown (Kd) macrophages have impaired mitochondrial respiratory function, which is further supported by down-regulation of genes encoding electron transport chain components and genes involved in fatty acid oxidation and mitochondrial function. Moreover, we observed Gbp1 is localized in both cytosol and mitochondrial fraction, and Gbp1 Kd macrophages display decreased mitophagy activity. More interestingly, Gbp1 Kd macrophages undergo senescence as evidenced by increased activation of AMPK-p53 pathway and positive staining of β-galactosidase. These observations suggest that Gbp1 may play an important role in protecting against mitochondrial dysfunction and preserving immune function of macrophages during inflammatory stress and aging.
AB - Macrophage polarization is tightly associated with its metabolic reprograming and immune dysfunction. However, the intracellular molecules/pathways that connect these alterations in inflammatory macrophages remain largely unidentified. Herein, we explored the role of guanylate binding protein 1 (Gbp1), an intracellular anti-microbial protein, in regulating polarization, metabolic reprogramming, and cellular aging of macrophages. We showed that Gbp1 expression in inguinal white adipose tissue is significantly decreased in high-fat diet -fed and aged mice. Gbp1 expression is significantly induced by IFNγ and LPS in macrophages but not adipocytes. Downregulation of Gbp1 expression causes macrophage polarization towards a pro-inflammatory phenotype. Gbp1 knockdown (Kd) macrophages have impaired mitochondrial respiratory function, which is further supported by down-regulation of genes encoding electron transport chain components and genes involved in fatty acid oxidation and mitochondrial function. Moreover, we observed Gbp1 is localized in both cytosol and mitochondrial fraction, and Gbp1 Kd macrophages display decreased mitophagy activity. More interestingly, Gbp1 Kd macrophages undergo senescence as evidenced by increased activation of AMPK-p53 pathway and positive staining of β-galactosidase. These observations suggest that Gbp1 may play an important role in protecting against mitochondrial dysfunction and preserving immune function of macrophages during inflammatory stress and aging.
UR - http://www.scopus.com/inward/record.url?scp=85041097547&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041097547&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-19828-7
DO - 10.1038/s41598-018-19828-7
M3 - Article
C2 - 29374208
AN - SCOPUS:85041097547
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 1679
ER -