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Epithelial cell-specific MyD88 signaling mediates ischemia/reperfusion-induced intestinal injury independent of microbial status.

ABSTRACT: The Toll-like receptor/MyD88 signaling pathway has been shown to mediate protective functions during intestinal exposure to various noxious events. The goal of this study was to define the role of bacteria and MyD88 signaling in intestinal response to damage using an ischemia-reperfusion (I/R)-induced injury model. We showed that conventionalized mice displayed a better outcome to I/R-induced injury than germ-free mice (3.8 ± 1.98 vs. 11.8 ± 1.83, P < 0.05). However, mice with intestinal epithelial cell (IEC)-specific deletion of Myd88 (Myd88) were protected from I/R-induced injury compared with Myd88 control mice. Myd88 mice also displayed a significantly reduced bacterial translocation (?85%) into lymph nodes compared with Myd88 mice. Expression of ccl2 and cxcl1 mRNA was significantly reduced (85% and 62%, respectively) in intestinal tissue of Myd88 mice compared with Myd88 mice, which associated with a reduced number of myeloperoxidase-positive cells in intestinal tissues of I/R-exposed Myd88 mice. Immunohistochemistry analysis showed a reduced IgA deposition and complement staining in ischemic tissue of Myd88 mice compared with Myd88 mice. These findings suggest that I/R-induced intestinal injury involves IEC-derived MyD88 signaling leading to increased IgA deposition/degradation, and complement activation in conjunction with an influx of neutrophils mediated by chemokine production.

SUBMITTER: Muhlbauer M

PROVIDER: S-EPMC4039295 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Epithelial cell-specific MyD88 signaling mediates ischemia/reperfusion-induced intestinal injury independent of microbial status.

Mühlbauer Marcus M Perez-Chanona Ernesto E Jobin Christian C

Inflammatory bowel diseases 20131201 13

The Toll-like receptor/MyD88 signaling pathway has been shown to mediate protective functions during intestinal exposure to various noxious events. The goal of this study was to define the role of bacteria and MyD88 signaling in intestinal response to damage using an ischemia-reperfusion (I/R)-induced injury model. We showed that conventionalized mice displayed a better outcome to I/R-induced injury than germ-free mice (3.8 ± 1.98 vs. 11.8 ± 1.83, P < 0.05). However, mice with intestinal epithel ...[more]

PMID: 24141713

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Project description:Intestinal ischemia-reperfusion (I/R) injury is a devastating complication when the blood supply is reflowed in ischemic organs. Gastrin has critical function in regulating acid secretion, proliferation, and differentiation in the gastric mucosa. We aimed to determine whether gastrin has an effect on intestinal I/R damage. Intestinal I/R injury was induced by 60-min occlusion of the superior mesenteric artery followed by 60-min reperfusion, and the rats were induced to be hypergastrinemic by pretreated with omeprazole or directly injected with gastrin. Some hypergastrinemic rats were injected with cholecystokinin-2 (CCK-2) receptor antagonist prior to I/R operation. After the animal surgery, the intestine was collected for histological analysis. Isolated intestinal epithelial cells or crypts were harvested for RNA and protein analysis. CCK-2 receptor expression, intestinal mucosal damage, cell apoptosis, and apoptotic protein caspase-3 activity were measured. We found that high gastrin in serum significantly reduced intestinal hemorrhage, alleviated extensive epithelial disruption, decreased disintegration of lamina propria, downregulated myeloperoxidase activity, tumor necrosis factor-?, and caspase-3 activity, and lead to low mortality in response to I/R injury. On the contrary, CCK-2 receptor antagonist L365260 could markedly impair intestinal protection by gastrin on intestinal I/R. Severe edema of mucosal villi with severe intestinal crypt injury and numerous intestinal villi disintegrated were observed again in the hypergastrinemic rats with L365260. The survival in the hypergastrinemic rats after intestinal I/R injury was shortened by L365260. Finally, gastrin could remarkably upregulated intestinal CCK-2 receptor expression. Our data suggest that gastrin by omeprazole remarkably attenuated I/R induced intestinal injury by enhancing CCK-2 receptor expression and gastrin could be a potential mitigator for intestinal I/R damage in the clinical setting.

Dataset Information

Epithelial cell-specific MyD88 signaling mediates ischemia/reperfusion-induced intestinal injury independent of microbial status.

Publications

Epithelial cell-specific MyD88 signaling mediates ischemia/reperfusion-induced intestinal injury independent of microbial status.

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