High-mobility group box protein-1 induces acute pancreatitis through activation of neutrophil extracellular trap and subsequent production of IL-1β.

Abstract

PURPOSE:

The aim of this study is to evaluate acute pancreatitis (AP)-associated NET activation mediated by a novel inflammatory mediator (high-mobility group box protein-1 [HMGB1]) and proinflammatory cytokine responses.

METHODS:

In this study, primary neutrophils, monocytes, and monocytic cell line Thp-1-derived macrophages were isolated and treated with HMGB1, lipopolysaccharide (LPS), adenosine triphosphate (ATP), and ATP + ATP inhibitor. The effects of HMGB1, ATP, and deoxyribonuclease (DNAse) were then examined for their in vivo effects using a newly established AP mouse model.

RESULTS:

The mRNA and protein levels of inflammasome and interleukin IL-1β in cells, blood, and pancreatic tissues were examined. Within-cell nuclear DNA signal, cell-free DNA concentration, and pancreatic tissue damage were investigated. Our study showed that HMGB1 triggers NET formation in neutrophils and promotes the activation of inflammasome complexes (the NLR family, pyrin domain containing 3, and NLRP3; ASC; and caspase-1); therefore, the production of IL-1β is induced in human monocytes/macrophages. HMGB1 and NET cooperatively stimulate IL-1β processing in macrophages. Furthermore, the AP mouse model confirmed these HMGB1-mediated molecular mechanisms in vivo and indicated that HMGB1 is required for NET activation.

CONCLUSIONS:

We found that NET inhibition reverses HMGB1-stimulated inflammasome activation and IL-1β production. HMGB1 thus leads to pancreatic injury through the activation of NET and subsequently induces IL-1β processing from neutrophils to pancreatic tissues. These findings demonstrate that HMGB1 and NET are new therapeutic targets for inflammation suppression in severe AP.

• Authors: Xingmao Wu, Zhenyu Yang, Haiyuan Wang, Yang Zhao, Xiaopeng Gao, Bin Zang
• Journal: Life sciences (Life Sci) Vol. 286 Pg. 119231 (Dec 01 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 33600865 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• HMGB1 Protein
• IL1B protein, human
• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human

Topics

• Acute Disease
• Extracellular Traps (metabolism)
• HMGB1 Protein (metabolism)
• Humans
• Inflammasomes (metabolism)
• Interleukin-1beta (biosynthesis)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Pancreatitis (etiology, metabolism)
• THP-1 Cells