Background Toll-like receptors (TLRs) detect endogenous ligands released after trauma and contribute to the proinflammatory response to injury. Post-traumatic mortality correlates with the extent of the immuno-inflammatory response to injury which is comprised of a complex regulation of innate and adaptive immune responses. Although TLRs are known to modulate innate immune responses, their role in the suppression of lymphocyte responses following traumatic tissue injury is unclear. Methods This study used a murine model of severe peripheral tissue injury, involving muscle crush injury and injection of fracture components, to evaluate the roles of TLR2, 4 and 9 in the early and delayed immuno-inflammatory phenotype. Post-traumatic immune dysfunction was measured in our trauma model using the following parameters: ex-vivo splenocyte proliferation, Th1 cytokine release and iNOS induction within splenic myeloid-derived suppressor cells (MDSC). Systemic inflammation and liver damage were determined by circulating interleukin-6 levels and hepatocellular injury. Results Suppression of splenocyte responses after injury was dependent on TLR4 and 9 signaling as was post-traumatic iNOS upregulation in splenic MDSC. TLR2 was found to have only a partial role through contribution to inhibition of splenocyte proliferation. This study also reveals the involvement of TLR2 and 4 in the initial systemic inflammatory response to traumatic tissue injury, however, this response was found to be TLR9-independent. Conclusions These findings demonstrate the previously unidentified role of TLR2, 4 and 9 in the T-cell associated immune dysfunction following traumatic tissue injury. Importantly, this study also illustrates that TLRs play differing and selective roles in both the initial proinflammatory response and adaptive immune response after trauma. Furthermore, the results in the TLR9-deficient mice establishes that the upregulation of early pro-inflammatory markers do not always correlate with the extent of sustained immune dysfunction. This suggests potential for targeted therapies that could limit the immune dysfunction through selective inhibition of receptor function following injury.
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