Cold-inducible RNA-binding protein promotes gut barrier dysfunction and visceral hypersensitivity via activating mast cells in IBS-D

Background: Cold-inducible RNA-binding protein (CIRP) is implicated in gut barrier function and various immune responses. Mast cells (MCs) have been found to play a key role in the pathogenesis of irritable bowel syndrome (IBS). However, the regulation of CIRP on MCs and its role in diarrhea predominant-irritable bowel syndrome (IBS-D) remains unclear. Methods: CIRP expression was evaluated in IBS-D mice, which were induced via acetic acid enema in combination with restraint stress (AA/RS). To explore the direct effect of CIRP on gut barrier function, visceral sensitivity and the activity of MCs, recombinant murine CIRP protein (rmCIRP) was administered via enema for 14 consecutive days. Subsequently, a systematic CIRP knockout (CIRP^−/−) mouse was constructed successfully to further verify the role of CIRP in IBS-D. Results: In present study, we found the expression of CIRP was significantly increased in IBS-D mice and corresponding cell models. Exogenous CIRP administration significantly exacerbated gut barrier dysfunction and visceral hypersensitivity, which were accompanied by the activation of MCs. Conversely, CIRP deficiency restored gut barrier function and reduced visceral sensitivity, which was associated with the inhibition of MCs activation. Further experiments revealed that C48/80, a MCs activator, eliminated the protective effect of CIRP deficiency in IBS-D mice. In addition, inhibition of TLR4 and TRPV1, respectively, eliminated the activation of CIRP on MCs. Conclusions: CIRP plays a crucial role in the pathophysiology of IBS-D. Targeting CIRP may represent a promising therapeutic strategy for IBS-D.