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

ABSTRACT: 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 Reg3?, Reg3?, 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.

SUBMITTER: Hammer AM

PROVIDER: S-EPMC5681896 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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

Hammer Adam M AM Morris Niya L NL Cannon Abigail R AR Khan Omair M OM Gagnon Robin C RC Movtchan Nellie V NV van Langeveld Ilse I Li Xiaoling X Gao Bin B Choudhry Mashkoor A MA

Shock (Augusta, Ga.) 20171201 6

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 ...[more]

PMID: 28498296

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Project description:BackgroundSepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Intestinal mucosal barrier injury is one of the important manifestations of sepsis. Interleukin-9 (IL-9) and IL-9-producing CD4(+) T cells were emerging pro-inflammatory mediators with development of intestinal injury. However, it is unclear whether IL-9 is related to the intestinal barrier injury of sepsis.MethodsTo investigate the roles of IL-9-producing CD4(+) T cells and IL-9 in the process of barrier injury in sepsis, serum IL-9-producing CD4(+) T cell percentages, IL-9, and D-lactate levels were measured in septic patients and controls. The markers of barrier function in serum and intestinal tissue were also collected in septic rats. Moreover, the barrier injury degree and survival rate of septic rats were also investigated after increasing or interfering with IL-9 expression.ResultsThe serum IL-9-producing CD4(+) T cell percentages, IL-9, and D-lactate levels were significantly higher in septic patients or rats than those in controls. IL-9-producing CD4(+) T cells and IL-9 levels were positively correlated with D-lactate levels and had a high predictive value of 28-day mortality in septic patients. The non-survivors had significantly higher serum T cell percentages, IL-9, and D-lactate levels compared with survivors. In septic rats, IL-9 increased the expression levels of D-lactate, whereas that decreased the expression levels of zonula occludens 1. Moreover, the barrier injury was aggravated or alleviated by increasing or interfering with IL-9 expression, respectively. Survival rate analysis also showed that IL-9 decreased the 14-day survival rate of septic rats.ConclusionIL-9 is closely related to intestinal mucosal barrier injury and mortality in sepsis. IL-9 blockade has the potential to improve the barrier injury in sepsis.Trial registrationThe study was registered at ClinicalTrials.gov (ID: NCT03791866, Date: December 2018).

Project description:Background: Interleukin-22 (IL-22) impacts the integrity of intestinal epithelia and has been associated with the development of colitis-associated cancer and inflammatory bowel diseases (IBD). Previous data suggest that IL-22 protects the mucosal barrier and promotes wound healing and barrier defect. We hypothesized, that IL-22 modulates cell polarity of intestinal epithelial cells (IECs) acting on tight junction assembly. The aim of the study was to investigate IL-22-dependent mechanisms in the reprogramming of intestinal epithelia. Methods: IECs were exposed to IL-22 at various concentrations. IECs in Matrigel® were grown to 3-dimensional cysts in the presence or absence of IL-22 and morphology and expression of polarity proteins were analyzed by confocal microscopy. Epithelial cell barrier (TER and sandwich assay) and TJ assembly analysis (calcium-switch assay) were performed. TJ and cell polarity protein expression were assessed by western blotting and confocal microscopy. Cell migration and invasion assays were performed. Induction of epithelial-mesenchymal transition (EMT) was assessed by RT-qPCR analysis and western blotting. Signaling pathway analyses were performed by phosphoblotting and functional assays after blocking STAT3 and ERK signaling pathways. Using the toxoplasma-model of terminal ileitis, IL-22-knock-out mice were compared to wild-type littermates, analyzed for barrier function using one-path-impedance-analysis and macromolecular flux (H3-mannitol, Ussing-chambers). Results: IECs exhibited a barrier defect after IL-22 exposure. TJ protein distribution and expression were severely impaired. Delayed recovery in the calcium-switch assay was observed suggesting a defect in TJ assembly. Analyzing the 3D-cyst model, IL-22 induced multi-lumen and aberrant cysts, and altered the localization of cell polarity proteins. Cell migration and invasion was caused by IL-22 as well as induction of EMT. Interestingly, only inhibition of the MAPK pathway, rescued the TJal barrier defect, while blocking STAT3 was relevant for cell survival. In addition, ileal mucosa of IL-22 deficient mice was protected from the barrier defect seen in Toxoplasma gondii-induced ileitis in wild type mice shown by significantly higher Re values and correspondingly lower macromolecule fluxes. Conclusion: IL-22 impairs intestinal epithelial cell barrier by inducing EMT, causing defects in epithelial cell polarity and increasing cell motility and cell invasion. IL-22 modulates TJ protein expression and mediates tight junctional (TJal) barrier defects via ERK pathway.

Dataset Information

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

Publications

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

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