title: Selective roles for toll-like receptors 2, 4, and 9 in systemic inflammation and immune dysfunction following peripheral tissue injury.
abstract: 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.
  
  
  CONCLUSIONS
  These findings demonstrate the previously unidentified role of TLR2, TLR4, and TLR9 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, 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.
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA. darwiches@upmc.edu
authors.forename: Sophie S
authors.initials: SS
authors.lastname: Darwiche
authors.forename: Xiangcai
authors.initials: X
authors.lastname: Ruan
authors.forename: Marcus K
authors.initials: MK
authors.lastname: Hoffman
authors.forename: Kent R
authors.initials: KR
authors.lastname: Zettel
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Tracy
authors.forename: Linda M I
authors.initials: LM
authors.lastname: Schroeder
authors.forename: Changchun
authors.initials: C
authors.lastname: Cai
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Hoffman
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Pape
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000818:Animals; D007109:Immunity / Q000276:immunology / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008099:Liver / Q000276:immunology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology; D017695:Soft Tissue Injuries / Q000276:immunology / Q000503:physiopathology*; D013154:Spleen / Q000166:cytology / Q000503:physiopathology; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology / Q000503:physiopathology*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9