IL-25 Improves Luminal Innate Immunity and Barrier Function During Parenteral Nutrition

Abstract

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 A2 (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. 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. 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 sPLA2 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). 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.