Down-regulated cylindromatosis enhances NF-κB activation and aggravates inflammation in HBV-ACLF patients

• Published in: Emerging microbes & infections Vol. 11; no. 1; pp. 1586 - 1601
• Main Authors: Zhang, Xueyun, Zhang, Yao, Zhou, Pu, Ai, Jingwen, Liu, Xiaoqin, Zhang, Quanbao, Wang, Zhengxin, Wang, Hongyan, Zhang, Wenhong, Zhang, Jiming, Huang, Yuxian
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 31.12.2022; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: acute-on-Chronic liver failure; Chemokines; chemotaxis; CYLD; Cytokines; Hepatitis B; Liver; Liver cirrhosis; NF-κB; Pathogenesis; RNA-sequencing; RNA-sequencing; Acute-On-Chronic Liver Failure; CYLD; NF-κB; chemotaxis
• ISSN: 2222-1751; 2222-1751
• DOI: 10.1080/22221751.2022.2077128

The pathogenesis of liver in patients with hepatitis B virus-associated acute chronic liver failure (HBV-ACLF) remains largely unknown. We aimed to elucidate the molecular mechanism underlying the pathogenesis of liver in HBV-ACLF patients by using multiple approaches including transcriptome analysis. We performed transcriptomic sequencing analysis on the liver of HBV-ACLF patients (n = 6), chronic hepatitis B (n = 6), liver cirrhosis (n = 6) and normal control (n = 5), then explored the potential pathogenesis mechanism in liver specimen from another 48 subjects and further validated the molecular and cellular mechanisms using THP-1 cells. RNA-sequencing data analysis indicated that, among the genes up-regulated in HBV-ACLF, genes related to inflammatory response and chemotaxis accounted for a large proportion of the total DEGs. A number of key chemokines (CCL2, CCL5, CCL20, CXCL5, CXCL6, CXCL8) and NF-ĸB pathway were identified to be robust in the liver samples from HBV-ACLF patients. Interestingly, cylindromatosis (CYLD) was found to be downregulated in the liver of HBV-ACLF patients, in line with the well-established role of CYLD in regulating most of the chemokines and pro-inflammatory cytokines (CCL2, CCL5, CCL20, CXCL5, CXCL6, CXCL8, IL-6, IL-1β) via inhibition of NF-ĸB. Indeed, the knockdown of CYLD resulted in sustained activation of NF-ĸB in macrophages and enhanced chemokines and inflammatory cytokines production, which in turn enhanced chemotactic migration of neutrophil, monocyte, T lymphocytes, and NK cell. In conclusions, down-regulated CYLD aggravated inflammatory cell chemotaxis through enhancing NF-κB activation in HBV-ACLF patients, thereby participating in the pathogenesis of HBV-ACLF injury.