Selective roles for toll-like receptors 2, 4, and 9 in systemic inflammation and immune dysfunction following peripheral tissue injury

Sophie S. Darwiche*, Xiangcai Ruan, Marcus K. Hoffman, Kent R. Zettel, Aaron P. Tracy, Linda M.I. Schroeder, Changchun Cai, Rosemary A. Hoffman, Melanie J. Scott, Hans Christoph Pape, Timothy R. Billiar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


BACKGROUND: Toll-like receptors (TLRs) detect endogenous ligands released after trauma and contribute to the proinflammatory response to injury. Posttraumatic mortality correlates with the extent of the immunoinflammatory response to injury that is composed 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, TLR4, and TLR9 in the early and delayed immunoinflammatory phenotype. Posttraumatic immune dysfunction was measured in our trauma model using the following parameters: ex vivo splenocyte proliferation, TH1 cytokine release, and iNOS (inducible nitric oxide synthase) induction within splenic myeloid-derived suppressor cells. 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 TLR9 signaling as was posttraumatic iNOS upregulation in splenic myeloid-derived suppressor cells. 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 TLR4 in the initial systemic inflammatory response to traumatic tissue injury; however, this response was found to be TLR9 independent. CONCLUSION: These findings demonstrate the previously unidentified role of TLR2, TLR4, and TLR9 in the T cellYassociated 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, results in TLR9-deficient mice establish that the upregulation of early proinflammatory markers do not always correlate with the extent of sustained immune dysfunction. This suggests potential for targeted therapies that could limit immune dysfunction through selective inhibition of receptor function following injury.

Original languageEnglish
Pages (from-to)1454-1461
Number of pages8
JournalJournal of Trauma and Acute Care Surgery
Issue number6
StatePublished - Jun 2013
Externally publishedYes


  • Immune dysfunction
  • Injury
  • Lymphocyte
  • Mouse
  • Toll-like receptor


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