TLR4 Has Both Positive and Negative Roles in Intestinal Ischemia/Reperfusion

Tiffany Moses and Sherry D. Fleming. Division of Biology, Kansas State University, Manhattan, KS

Background: Mesenteric ischemia/reperfusion (IR) induces significant inflammation and immune-mediated damage which is repaired with time.  Toll-like receptor 4 (TLR4) is a critical protein in the induction of the inflammatory response and plays a role in intestinal homeostasis. We hypothesized that TLR4 may have a role in both IR-induced intestinal damage and repair.

Method: To test this hypothesis, we performed IR studies using TLR4 deficient and TLR4 mutant mice and analyzed mucosal damage, inflammatory response and epithelial repair. 

Results: We found that the absence of TLR4 or TLR4 –induced signaling led to attenuated local mucosal damage with significantly decreased prostaglandin E2 production. In addition, the limited damage which did occur was not repaired in the absence of TLR4 signaling. These results were confirmed when IR induced similar results in MyD88-/- mice which are deficient in the primary TLR adaptor protein.

Discussion: These data indicate a negative role for TLR4 signaling through MyD88 in IR-induced mucosal damage but a positive role in the subsequent epithelial repair in response to IR. Therefore, the timing and location of TLR4 expression is critical to both processes.

Acknowledgements: NIH IDeA Grants P20 RR017686 and RR016475 and AI061691, American Heart Association, NSF SBE-0244984, KSU Cancer Center and Division of Biology. Any opinions, findings, and conclusions expressed are the authors and not the views of NSF or NIH.

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