• Molecular immunology · Nov 2020

    The interaction between C/EBPβ and TFAM promotes acute kidney injury via regulating NLRP3 inflammasome-mediated pyroptosis.

    • Xin-Gui Dai, Qiong Li, Tao Li, Wei-Bo Huang, Zhen-Hua Zeng, Yang Yang, Ze-Peng Duan, Yu-Jing Wang, and Yu-Hang Ai.
    • Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha 410008, PR China; Department of Critical Care Medicine, The First People's Hospital of Chenzhou, Chenzhou 423000, PR China.
    • Mol. Immunol. 2020 Nov 1; 127: 136-145.

    AbstractSepsis-induced inflammatory damage is a crucial cause of acute kidney injury (AKI), and AKI is an ecumenical fearful complication in approximately half of patients with sepsis. CCAAT/enhancer-binding protein β (C/EBPβ) plays roles in regulating acute phase responses and inflammation. However, the role and mechanism of C/EBPβ in AKI are unclear. LPS combined with ATP-treated renal epithelial cells HK2 and cecal ligation-peferation (CLP)-mice were used as models of AKI in vitro and in vivo. Cell damage, the secretion of interleukin-1 beta (IL-1β), IL-18 and cysteinyl aspartate specific proteinase 1 (caspase-1) activity were tested by LDH, ELISA assay and flow cytometry analysis, respectively. The expression levels of TFAM, C/EBPβ, and pyroptosis-related molecules were tested by qRT-PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assessed the interaction between C/EBPβ with TFAM. Hematoxylin-Eosin (H&E) staining detected pathological changes of kidney tissues, and immunohistochemistry measured TFAM and C/EBPβ in mice kidney tissues. C/EBPβ or TFAM were up-regulated in LPS combined with ATP -induced HK2 cells. Knockdown of C/EBPβ could suppress cell injury and the secretion of IL-1β and IL-18 induced by LPS combined with ATP. Furthermore, C/EBPβ up-regulated the expression levels of TFAM via directly binding to TFAM promoter. Overexpression of TFAM reversed the effects of C/EBPβ deficiency on pyroptosis. Knockdown of C/EBPβ could inhibit NLRP3 inflammasome-mediated caspase-1 signaling pathway by inactivating TFAM/RAGE pathway. It was further confirmed in the AKI mice that C/EBPβ and TFAM promoted AKI by activating NLRP3-mediated pyroptosis. The interaction of between C/EBPβ and TFAM facilitated pyroptosis by activating NLRP3/caspase-1 signal axis, thereby promoting the occurrence of AKI.Copyright © 2020 Elsevier Ltd. All rights reserved.

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