Toll-like receptor 2 deficiency alleviates acute pancreatitis by inactivating the NF-κB/NLRP3 pathway

Lingyun Li; Qiang Liu; Chenyu Le; Hongchen Zhang; Wenfei Liu; Ye Gu; Jianfeng Yang; Xiaofeng Zhang

doi:10.1016/j.intimp.2023.110547

Toll-like receptor 2 deficiency alleviates acute pancreatitis by inactivating the NF-κB/NLRP3 pathway

Int Immunopharmacol. 2023 Aug:121:110547. doi: 10.1016/j.intimp.2023.110547. Epub 2023 Jun 23.

Authors

Lingyun Li¹, Qiang Liu¹, Chenyu Le², Hongchen Zhang³, Wenfei Liu⁴, Ye Gu³, Jianfeng Yang⁵, Xiaofeng Zhang⁶

Affiliations

¹ Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Disease, Hangzhou 310006, China.
² The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China.
³ Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China.
⁴ Chinese PLA 305 Hospital, Beijing 100018, China.
⁵ Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Disease, Hangzhou 310006, China.
⁶ Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Disease, Hangzhou 310006, China. Electronic address: zxf837@tom.com.

PMID: 37356124
DOI: 10.1016/j.intimp.2023.110547

Abstract

The early aseptic immune response is the key factor leading to the aggravation of acute pancreatitis (AP). Toll-like receptor (TLR) 2 is an important member of the TLR family, but the role of TLR2 in AP remains to be investigated. In the present study, we found that TLR2 expression was significantly increased in AP patients. In a mouse model of cerulein-induced AP, TLR2 deficiency resulted in reduced inflammation, reduced infiltration of pancreatic neutrophils and macrophages, and decreased expression of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-17 and IL-18. In addition, transcriptomic analysis revealed that nod-like receptor family pyrin domain-containing 3 (NLRP3) expression was increased in AP, and there was a significant correlation between NLRP3 and TLR2. This study found that TLR2 deficiency can lead to a decrease in the activation of the NF-κB/NLRP3 signalling pathway, and the NLRP3 inhibitor MCC950 can alleviate AP in mice. Therefore, this study confirmed that TLR2 participates in the development of AP by activating the NF-κB/NLRP3 pathway. This study suggested that TLR2 might be a novel therapeutic target for AP.

Keywords: Acute pancreatitis; HMGB1; NF-κB; NLRP3 inflammasome; TLR2.

MeSH terms

Acute Disease
Animals
Humans
Inflammasomes / metabolism
Mice
NF-kappa B* / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Pancreatitis* / chemically induced
Pancreatitis* / metabolism
Toll-Like Receptor 2 / genetics
Toll-Like Receptor 2 / metabolism

Substances

Inflammasomes
NF-kappa B
NLR Family, Pyrin Domain-Containing 3 Protein
Toll-Like Receptor 2
Tlr2 protein, mouse