Abstract
Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators such as TNF-α and ICAM-1.
Highlights
Ischemia-reperfusion (I/R) injury of the small intestine occurs in a variety of clinical conditions, including small bowel occlusion and thrombosis of mesenteric artery, vascular surgery, shock, small bowel transplantation, and trauma [1]
Toll-like receptor 2 (TLR2) deficiency prevented I/R-induced apoptosis of the small intestinal epithelial cells (Figure 1D): The apoptotic indices of TLR2 KO mice were reduced by 43% compared with those of wild-type mice (Figure 1E)
The results suggest that the TLR2dependent pathway mediates I/R injury in adult mice, and that the roles of TLR2 in intestinal I/R injury may differ with age
Summary
Ischemia-reperfusion (I/R) injury of the small intestine occurs in a variety of clinical conditions, including small bowel occlusion and thrombosis of mesenteric artery, vascular surgery, shock, small bowel transplantation, and trauma [1]. Reperfusion after ischemia in the small intestine initiates inflammatory responses, resulting in cell and tissue injuries. Gastrointestinal I/R causes intestinal dysmotility, which is associated with the disruption of the interstitial cells of Cajal network [3] and changes in synthesis of several endogenous mediators such as ghrelin [4], which induces bacterial overgrowth and bacterial translocation from the gastrointestinal tract. These phenomena lead to systemic inflammation and produce the multiple organ dysfunction syndrome. Several inflammatory pathways are postulated to modulate inflammation during intestinal I/R injury [5,6,7,8], the precise mechanisms of I/R-induced inflammations remain unclear
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