Pancreatic fibrosis is an important pathogenesis of chronic pancreatitis (CP), and the activation of pancreatic stellate cells (PSCs) caused by chronic inflammation plays a key role in this process. Cold-inducible RNA-binding protein (CIRP) is a stress response protein involved in acute inflammation and tissue fibrosis. However, its role in pancreatic fibrosis has not been elucidated. Serum CIRP levels were measured in 17 CP patients and 34 healthy controls. Two mouse models of CP (intraperitoneal administration of L-arginine or cerulein) were employed for in vivo studies. CIRP gene knockout (Cirp-KO) was utilized to downregulate CIRP in mice. C23, a specific inhibitor of CIRP, was used to antagonize CIRP activity in experimental CP. NLRP3 inhibitors or disulfiram were used to block pancreatic cell pyroptosis in CP mice. Serum CIRP levels were elevated in both CP patients and in a mouse model of CP. This increase in CIRP was positively correlated with the severity of pancreatic fibrosis and pyroptosis in experimental CP. Genetic deletion of CIRP or intraperitoneal administration of C23 mitigated pancreatic fibrosis in CP mice. Mechanistically, the pro-fibrotic effects of CIRP appear to be mediated through the TLR4 receptor and the induction of pyroptosis. Accordingly, specific inhibition of TLR4 or blockade of pyroptosis effectively reduced pancreatic inflammation and fibrosis in CP mice, without altering serum CIRP levels. Collectively, our data indicate that CIRP plays a significant role in experimental CP. Inhibition of CIRP alleviates pyroptosis and ameliorates the inflammatory microenvironment in pancreatic tissue, thereby retarding the progression of pancreatic fibrosis. This study primarily provides preclinical evidence elucidating a novel mechanism, and the translational relevance to human disease requires further validation.
Cui et al. (Sat,) studied this question.