IL-25 improves luminal innate immunity and barrier function during parenteral nutrition

摘要

BACKGROUND:: Parenteral nutrition (PN) increases risks of infections in critically injured patients. Recently, PN was shown to reduce intestine luminal levels of the Paneth cell antimicrobial molecule secretory phospholipase A 2 (sPLA2) and the goblet cell glycoprotein mucin2 (MUC2). These molecules are critical factors for innate mucosal immunity and provide barrier protection. Interleukin-4 (IL-4) and IL-13 regulate sPLA2 and MUC2 production through the IL-13 receptor. Because IL-25 stimulates IL-4 and IL-13 release and PN reduces luminal sPLA2 and MUC2, we hypothesized that adding IL-25 to PN would restore these innate immune factors and maintain barrier function. METHODS:: Two days after venous cannulation, male ICR (Institute of Cancer Research) mice were randomized to receive chow (n = 12), PN (n = 9), or PN + 0.7 μg of exogenous IL-25 (n = 11) daily for 5 days. Small-intestine wash fluid (SIWF) was collected for analysis of sPLA2 activity, MUC2 density, and luminal levels of IL-4 and IL-13. Small-intestinal tissue was harvested for analysis of tissue sPLA2 activity or immediate use in an ex-vivo intestinal segment culture (EVISC) to assess susceptibility of the tissue segments to enteroinvasive Escherichia coli. RESULTS:: PN reduced luminal sPLA2 (P 0.0001) and MUC2 (P 0.002) compared with chow, whereas the addition of IL-25 to PN increased luminal sPLA2 (P 0.0001) and MUC2 (P 0.02) compared with PN. Tissue IL-4 and IL-13 decreased with PN compared with chow (IL-4: P 0.0001, IL-13: P 0.002), whereas IL-25 increased both cytokines compared with PN (IL-4: P 0.03, IL-13: P 0.02). Tissue levels of sPLA 2 were significantly decreased with PN compared with chow, whereas IL-25 significantly increased tissue sPLA2 levels compared with PN alone. Functionally, more bacteria invaded the PN-treated tissue compared with chow (P 0.01), and the addition of IL-25 to PN decreased enteroinvasion to chow levels (P 0.01). CONCLUSIONS:: PN impairs innate mucosal immunity by suppressing luminal sPLA2 activity and MUC2 density compared with chow. PN also increases bacterial invasion in ex-vivo tissue. Administration of exogenous IL-25 reverses this dysfunction and increases luminal sPLA2 and MUC2. PN tissue treated with IL-25 was significantly more resistant to bacterial invasion than with PN alone, suggesting that IL-25-induced effects augment the barrier defense mechanisms.