Activation of BZW1 by CEBPB in macrophages promotes eIF2α phosphorylation-mediated metabolic reprogramming and endoplasmic reticulum stress in MRL/lpr lupus-prone mice

Cellular & Molecular Biology Letters

Research

Huimeng Qi¹  Zhaoguo Zheng²  Qiang Liu² 

[1] Department of General Practice, Fuyang Hospital of Anhui Medical University, 236000, Fuyang, Anhui, People’s Republic of China;Department of Nephrology, Guangdong Second Provincial General Hospital, Haizhu District, No. 466, Xingang Zhong, 510317, Guangzhou, Guangdong, People’s Republic of China;

关键词: CEBPB;    BZW1;    Glycolysis;    Endoplasmic reticulum stress;    Lupus nephritis;   

DOI  :  10.1186/s11658-023-00494-1

 received in 2023-06-14, accepted in 2023-09-26,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLupus nephritis (LN) is associated with significant mortality and morbidity, while effective therapeutics and biomarkers are limited since the pathogenesis is complex. This study investigated the roles of the CEBPB/BZW1/eIF2α axis in metabolic reprogramming and endoplasmic reticulum stress in LN.MethodThe differentially expressed genes in LN were screened using bioinformatics tools. The expression of CEBPB in the renal tissue of patients with LN and its correlation with the levels of creatinine and urinary protein were analyzed. We used adenoviral vectors to construct LN mice with knockdown CEBPB using MRL/lpr lupus-prone mice and analyzed the physiological and autoimmune indices in mice. Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP–qPCR) and dual-luciferase reporter assays were conducted to explore the regulation of BZW1 by CEBPB, followed by glycolytic flux analysis, glucose uptake, and enzyme-linked immunosorbent assay (ELISA). Finally, the role of eIF2α phosphorylation by BZW1 in bone marrow-derived macrophages (BMDM) was explored using eIF2α phosphorylation and endoplasmic reticulum stress inhibitors.ResultsCEBPB was significantly increased in renal tissues of patients with LN and positively correlated with creatinine and urine protein levels in patients. Downregulation of CEBPB alleviated the autoimmune response and the development of nephritis in LN mice. Transcriptional activation of BZW1 by CEBPB-mediated glucose metabolic reprogramming in macrophages, and upregulation of BZW1 reversed the mitigating effect of CEBPB knockdown on LN. Regulation of eIF2α phosphorylation levels by BZW1 promoted endoplasmic reticulum stress-amplified inflammatory responses in BMDM.ConclusionTranscriptional activation of BZW1 by CEBPB promoted phosphorylation of eIF2α to promote macrophage glycolysis and endoplasmic reticulum stress in the development of LN.

【 授权许可】

CC BY   
© University of Wroclav 2023

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