Calcitonin gene-related peptide ameliorates sepsis-induced intestinal injury by suppressing NLRP3 inflammasome activation

Intestinal damage has long been viewed as the primary cause of sepsis-induced multiple organ dysfunction syndrome (MODS). Previous studies have demonstrated that Calcitonin gene-related peptide (CGRP) exhibits anti-inflammatory and protective effects in mice exposed to endotoxin. This study investigated whether CGRP protects against sepsis-induced intestinal damage and its underlying mechanisms. Using a murine caecal ligation and puncture (CLP) model, we observed elevated serum and intestinal CGRP levels in septic mice. CGRP knockout (KO) mice showed more severe intestinal barrier damage, excessive NLRP3 inflammasome activation and higher levels of inflammation. In vitro, we used lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to activate the NLRP3 inflammasome in MODE-K murine intestinal epithelial cells. CGRP inhibited NF-κB pathway activation; prevented ASC assembly and ROS accumulation; significantly decreased NLRP3, Caspase-1 p10, and IL-1β levels and LDH release; and increased cell viability. Treatment with an IL-1β inhibitor or CGRP suppressed p38 MAPK and ERK1/2 pathway activation and increased ZO-1 and Occludin protein levels in LPS+ATP-treated MODE-K cells. Finally, we used the CGRP upstream agonist drug rutaecarpine (RUT) to control endogenous CGRP release in mice, and this drug demonstrated good therapeutic effects on septic intestinal injury. In conclusion, our results suggest that CGRP ameliorates sepsis-induced intestinal damage, providing valuable insights for drug development.

Calcitonin gene-related peptide; Inflammation; Intestinal injury; NLRP3 inflammasome; Sepsis.