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
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.