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Interleukin-22 Prevents Microbial Dysbiosis and Promotes Intestinal Barrier Regeneration Following Acute Injury

2017; Lippincott Williams & Wilkins; Volume: 48; Issue: 6 Linguagem: Inglês

10.1097/shk.0000000000000900

1540-0514

Adam M. Hammer, Niya L. Morris, Abigail R. Cannon, Omair Khan, Robin C. Gagnon, Nellie V. Movtchan, Ilse van Langeveld, Xiaoling Li, Bin Gao, Mashkoor A. Choudhry,

Vitamin C and Antioxidants Research

Intestine barrier disruption and bacterial translocation can contribute to sepsis and multiple organ failure, leading causes of mortality in burn-injured patients. In addition, findings suggest that ethanol (alcohol) intoxication at the time of injury worsens symptoms associated with burn injury. We have previously shown that interleukin-22 (IL-22) protects from intestinal leakiness and prevents overgrowth of gram-negative bacteria following ethanol and burn injury, but how IL-22 mediates these effects has not been established. Here, utilizing a mouse model of ethanol and burn injury, we show that the combined insult results in a significant loss of proliferating cells within small intestine crypts and increases Enterobacteriaceae copies, despite elevated levels of the antimicrobial peptide lipocalin-2. IL-22 administration restored numbers of proliferating cells within crypts, significantly increased Reg3β, Reg3γ, lipocalin-2 AMP transcript levels in intestine epithelial cells, and resulted in complete reduction of Enterobacteriaceae in the small intestine. Knockout of signal transducer and activator of transcription factor-3 (STAT3) in intestine epithelial cells resulted in complete loss of IL-22 protection, demonstrating that STAT3 is required for intestine barrier protection following ethanol combined with injury. Together, these findings suggest that IL-22/STAT3 signaling is critical to gut barrier integrity and targeting this pathway may be of beneficial clinical relevance following burn injury.