Date: Monday, June 3, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Critical roles of CCAAT-Enhancer-Binding Protein Homologous Protein (CHOP) have been found in mediating acute liver injury. The aim of this study is to determine the underlying mechanism of CHOP signaling in regulating innate immune activation and liver injury in a toxin-induced liver injury model.
*Methods: Wild-type (WT) and CHOP KO mice were subjected to a murine thioacetamide (TAA) induced acute liver injury model. Liver injury and intrahepatic inflammation were compared between groups. Bone-marrow derived macrophages (BMDMs) were isolated from WT and KO mice, and the macrophage M1/M2 phenotype was determined in vitro. Autophagy and its regulatory signaling pathways were analyzed as well.
*Results: CHOP KO significantly decreased liver injury, as evidenced by lower sALT levels and better preserved liver architectures. CHOP KO mice demonstrated significantly increased intrahepatic inflammation. BMDMs from CHOP KO mice secreted much higher levels of TNF-a and IL-6, but lower levels of IL-10. CHOP KO also promoted macrophage M2 polarization as shown by increased Arg1 gene induction and CD206 staining. Interestingly, CHOP KO BMDMs showed enhanced autophagy activation as shown by LC3B staining and transmission electron microscope detection. Signaling pathway analysis revealed that ATG5 activation was enhanced in CHOP KO BMDMs. Furthermore, ATG5 knockdown by siRNA increased pro-inflammatory activation and inhibited M2 polarization in CHOP KO BMDMs. Finally, in vivo ATG5 knockdown in macrophages increased intrahepatic inflammation and liver injury in CHOP KO mice.
*Conclusions: Our results indicated that CHOP deficiency promoted macrophage M2 polarization and protected livers against TAA-induced liver injury. ATG5-mediated autophagy was critical for regulating macrophage M2 activation by CHOP KO. Strategies targeting CHOP or autophagy signaling in macrophages may provide therapeutic effects against liver acute injury in patients.
To cite this abstract in AMA style:Zhou H, Liu R, Wang Q, Shi C, Cheng F, Wang X, Lu L. CHOP Deficiency Attenuated Acute Liver Injury by Promoting Macrophage M2 Polarization via ATG5-Mediated Autophagy Activation [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/chop-deficiency-attenuated-acute-liver-injury-by-promoting-macrophage-m2-polarization-via-atg5-mediated-autophagy-activation/. Accessed March 1, 2021.
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