LincRNA‐EPS alleviates severe acute pancreatitis by suppressing HMGB1‐triggered inflammation in pancreatic macrophages

• Published in: Immunology 2021-06, Vol.163 (2), p.201-219
• Main Authors: Chen, Shengchuan, Zhu, Jingfei, Sun, Li‐Qiong, Liu, Siying, Zhang, Tan, Jin, Yuepeng, Huang, Chaohao, Li, Dapei, Yao, Haiping, Huang, Jian, Qin, Yanghua, Zhou, Mengtao, Chen, Gang, Zhang, Qiyu, Ma, Feng
• Format: Article
• Language: English
• Subjects: Acinar cells; Animal models; Cytokines; Edema; Genes; HMGB1; HMGB1 protein; Inflammation; Inflammatory diseases; Inflammatory response; lincRNA‐EPS; lncRNA; Macrophages; Multiple organ dysfunction syndrome; NF‐κB; Non-coding RNA; Organs; Original; Pancreas; Pancreatitis; severe acute pancreatitis; Systemic inflammatory response syndrome; Therapeutic applications; TLR4 protein; Toll-like receptors; Tumor necrosis factor
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13313

Summary Acute pancreatitis (AP), an inflammatory disorder of the pancreas with a high hospitalization rate, frequently leads to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). However, therapeutic targets for effective treatment and early intervention of AP are still urgently required to be identified. Here, we have observed that the expression of pancreatic lincRNA‐EPS, a long intergenic non‐coding RNA, is dynamically changed during both caerulein‐induced AP (Cer‐AP) and sodium taurocholate‐induced severe AP (NaTc‐SAP). The expression pattern of lincRNA‐EPS is negatively correlated with the typical inflammatory genes such as IL‐6, IL‐1β, CXCL1, and CXCL2. Further studies indicate that knockout of lincRNA‐EPS aggravates the pathological symptoms of AP including more induction of serum amylase and lipase, severe edema, inflammatory cells infiltration and acinar necrosis in both experimental AP mouse models. Besides these intrapancreatic effects, lincRNA‐EPS also protects against tissue damages in the extra‐pancreatic organs such as lung, liver, and gut in the NaTc‐SAP mouse model. In addition, we have observed more serum pro‐inflammatory cytokines TNF‐α and IL‐6 in the lincRNA‐EPS‐/‐ NaTc‐SAP mice and more extracellular HMGB1 around injured acinar cells in the pancreas from lincRNA‐EPS‐/‐ NaTc‐SAP mice, compared with their respective controls. Pharmacological inhibition of NF‐κB activity by BAY11‐7082 significantly abolishes the suppressive effect of lincRNA‐EPS on TLR4 ligand‐induced inflammatory genes in macrophages. Our study has described a protective role of lincRNA‐EPS in alleviating AP and SAP, outlined a novel pathway that lincRNA‐EPS suppresses HMGB1‐NF‐κB‐dependent inflammatory response in pancreatic macrophages and provided a potential therapeutic target for SAP. Injured acinar cells release a large amount of HMGB1 during Cer‐AP and NaTc‐SAP. HMGB1 activates the TLR4‐dependent downstream signalling in the pancreatic macrophages to produce pro‐inflammatory cytokines and chemokines, and thus leads to neutrophils and macrophages infiltration, and local and systemic inflammation. lincRNA‐EPS, downregulated at the initial stage of Cer‐AP and NaTc‐SAP, plays an important role in restricting the production of pro‐inflammatory cytokines and chemokines in pancreatic macrophages by targeting the HMGB1‐TLR4‐NF‐κB signalling pathway.