Adipose-Derived Mesenchymal Stem Cell Exosomes Encapsulating siIL1R2 Facilitate the Repair of DSS-Induced Intestinal Mucosal Injury.

Abstract

Background: Interleukin-1 receptor 2 (IL1R2) and C-C motif chemokine receptor 2 (CCR2) as critical mediators of immune modulation and inflammation. This study aims to evaluate their functions in dextran sulfate sodium (DSS)-induced intestinal injury.

Methods: A DSS-induced intestinal injury model was established in C57BL/6 mice. Pharmacological inhibitors targeting IL1R2 or CCR2 were administered. Adipose-derived mesenchymal stem cell (ADMSC)-derived exosomes were isolated and loaded with IL1R2-siRNA, which were then administered to intestinal epithelial cells (IEC-6) or DSS-challenged mice.

Results: IL1R2 and CCR2 were upregulated in DSS-treated colon tissues. Pharmacological inhibition of IL1R2 or CCR2 improved body weight, restored colon length, reduced serum TNF-α and IL-6 levels, and preserved epithelial integrity in mice. miR-128-3p enriched in ADMSC-derived exosomes significantly reduced CCR2 expression in IEC-6 cells. Further loading of an IL1R2 siRNA in these exosomes led to a simultaneous inhibition of IL1R2. These exosomes reduced lipopolysaccharide-induced apoptosis and inflammation in IEC-6 cells and improved histological outcomes in DSS-challenged mice.

Conclusion: IL1R2 and CCR2 are key mediators of inflammation in DSS-induced intestinal injury. Dual inhibition of IL1R2 and CCR2 holds great promise for alleviating inflammatory responses and improving histological presentations in inflammatory bowel disease.