Targeting extracellular CIRP with an X-aptamer shows therapeutic potential in acute pancreatitis

Wuming Liu; Jianbin Bi; Yifan Ren; Huan Chen; Jia Zhang; Tao Wang; Mengzhou Wang; Lin Zhang; Junzhou Zhao; Zheng Wu; Yi Lv; Bing Liu; Rongqian Wu

doi:10.1016/j.isci.2023.107043

Targeting extracellular CIRP with an X-aptamer shows therapeutic potential in acute pancreatitis

iScience. 2023 Jun 7;26(7):107043. doi: 10.1016/j.isci.2023.107043. eCollection 2023 Jul 21.

Authors

Wuming Liu^{1

2}, Jianbin Bi^{1

3}, Yifan Ren^{1

4}, Huan Chen⁵, Jia Zhang^{1

6}, Tao Wang^{1

2}, Mengzhou Wang^{1

2}, Lin Zhang^{1

2}, Junzhou Zhao^{1

2}, Zheng Wu², Yi Lv^{1

2}, Bing Liu⁵, Rongqian Wu¹

Affiliations

¹ National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
² Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
³ Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁴ Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁵ BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁶ Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Abstract

Severe acute pancreatitis (AP) is associated with a high mortality rate. Cold-inducible RNA binding protein (CIRP) can be released from cells in inflammatory conditions and extracellular CIRP acts as a damage-associated molecular pattern. This study aims to explore the role of CIRP in the pathogenesis of AP and evaluate the therapeutic potential of targeting extracellular CIRP with X-aptamers. Our results showed that serum CIRP concentrations were significantly increased in AP mice. Recombinant CIRP triggered mitochondrial injury and ER stress in pancreatic acinar cells. CIRP^-/- mice suffered less severe pancreatic injury and inflammatory responses. Using a bead-based X-aptamer library, we identified an X-aptamer that specifically binds to CIRP (XA-CIRP). Structurally, XA-CIRP blocked the interaction between CIRP and TLR4. Functionally, it reduced CIRP-induced pancreatic acinar cell injury in vitro and L-arginine-induced pancreatic injury and inflammation in vivo. Thus, targeting extracellular CIRP with X-aptamers may be a promising strategy to treat AP.

Keywords: Biomolecular engineering; Cell biology; Molecular physiology; Pathophysiology.