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

ABSTRACT

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.

KEYWORDS:

• RNA-sequencing
• acute-on-Chronic liver failure
• CYLD
• NF-κB
• chemotaxis

Acknowledgements

Thanks to Prof. Zunguo Du from the Department of Pathology, Huashan Hospital, Fudan University for helping with histological analysis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No.81670560, 81871640, 82172255), National Science and Technology Major Project (2017ZX09304005, 2017ZX10202202), Shanghai Shen Kang Hospital Development Center (No. SHDC12021114, No. SHDC12019116), Shanghai Key Clinical Specialty Construction Program (ZK2019B24) and Shanghai Municipal Science and Technology Major Project (HS2021SHZX001).

The funders had no role in the design, conduct, or reporting of the study.