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ASSA14-03-25 Cellular repressor of E1A-stimulated genes antagonises inflammation and promotes autophagy via lysosome biogenesis in mouse macrophages
  1. M Sun,
  2. C Yan,
  3. X Tian,
  4. Y Li,
  5. J Tao,
  6. Y Han
  1. Department of Cardiology, Institute of Cardiovascular Research of People’s Liberation Army, Shenyang Northern Hospital, Shenyang, Liaoning 110840, China

Abstract

Objective Macrophage inflammation plays an important role in the pathogenesis of atherosclerosis. In this study, we investigated the involvement of cellular repressor of E1A-stimulated genes (CREG) in tumour necrosis factor-α (TNF-α)-induced macrophage inflammation, and explored its inhibitory capacity and mechanisms to assess its potential as a therapeutic reagent for atherosclerosis.

Methods and results We confirmed that CREG played an important role in TNF-α-induced macrophage inflammation and had anti-inflammatory effects in RAW 264.7 mouse macrophages induced by TNF-α, using enzyme-linked immunosorbent assays and western blotting. Gain-of-function and loss-of-function experiments revealed that CREG promoted autophagy in TNF-α-induced RAW 264.7 cells. Using the autophagy inhibitors 3-methyladenine and bafilomycin A, we demonstrated that autophagy played an important role in attenuating TNF-α-induced inflammation. Immunofluorescence analysis and western blotting showed that CREG protein stimulated the expression and maturation of cathepsin B and cathepsin L and induced the biogenesis of lysosomes, while CREG deficiency reduced lysosome biogenesis. Exogenous CREG protein was located in lysosomes, as shown by confocal microscopy and immunoprecipitation analysis. CREG protein played a critical role in the distribution but not in the expression of mannose-6-phosphate/insulin-like growth factor II receptor (M6P/IGFIIR), as demonstrated by western blotting and immunofluorescence analysis. In vivo experiments indicated that CREG protein alleviated the development of aortic atherosclerosis and affected inflammation and autophagy in aortas of ApoE−/− mice.

Conclusion CREG inhibits macrophage inflammation and promotes autophagy mediated by lysosome biogenesis, which is related to the distribution of M6P/IGFIIR. CREG may represent a new therapeutic target against atherosclerosis.

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