Activation of the MyD88 signaling pathway inhibits ischemia-reperfusion injury in the small intestine

Abstract

Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates innate and adaptive immunity. Recent studies have shown that the activation of TLR-dependent signaling pathways plays important roles in the pathogenesis of ischemia-reperfusion (I/R) injuries in many organs. All TLRs, except TLR3, use a common adaptor protein, MyD88, to transduce activation signals. We investigated the role of MyD88 in I/R injury of the small intestine. MyD88 and cyclooxygenase-2 (COX-2) knockout and wild-type mice were subjected to intestinal I/R injury. I/R-induced small intestinal injury was characterized by infiltration of inflammatory cells, disruption of the mucosal epithelium, destruction of villi, and increases in myeloperoxidase activity and mRNA levels of TNF-α and the IL-8 homolog KC. MyD88 deficiency worsened the severity of I/R injury, as assessed using the histological grading system, measuring luminal contents of hemoglobin (a marker of intestinal bleeding), and counting apoptotic epithelial cells, while it inhibited the increase in mRNA expression of TNF-α and KC. I/R significantly enhanced COX-2 expression and increased PGE(2) concentration in the small intestine of wild-type mice, which were markedly inhibited by MyD88 deficiency. COX-2 knockout mice were also highly susceptible to intestinal I/R injury. Exogenous PGE(2) reduced the severity of injury in both MyD88 and COX-2 knockout mice to the level of wild-type mice. These findings suggest that the MyD88 signaling pathway may inhibit I/R injury in the small intestine by inducing COX-2 expression.

Depletion of enteric bacteria diminishes leukocyte infiltration following doxorubicin-induced small intestinal damage in mice

“…[16–18] Interestingly, some studies suggest that the presence of enteric bacteria protects from the development damage, while others suggest that the presence of enteric bacteria is detrimental and contributes to inflammation and damage. Others have explored the murine response to Doxo in models of limited bacterial signaling.…”

Role of cyclooxygenase-2 in intestinal injury in neonatal rats

“…TLR4 and MyD88 signaling are required for optimal proliferation and protection against apoptosis in the injured intestine (17). MyD88 deficiency has been shown to aggravate intestinal ischemia/reperfusion injury and inhibit increases in COX-2 expression and prostaglandin E2 synthesis during the development of injury (20). LPS-induced COX-2 expression stimulates the proliferation of colonocytes and repair of colonic epithelium, therefore LPS stimulation of COX-2 was protective in experimental NEC (7).…”

Membrane lipid interactions in intestinal ischemia/reperfusion-induced Injury

“…It is well established that the expression of Cox 2, the inducible isoform, is elevated in the intestinal tissue following ischemia. Several animal models have demonstrated an increase in Cox 2 transcription and translation in the intestine following varying lengths of ischemia and reperfusion [13–18]. The use of Cox inhibitors, NS-398 and FK3311, has further demonstrated the importance of this pathway in reperfusion injury in some but not all animal models [14, 19].…”