• Sebastian Korff, Patricia Loughran, Changchun Cai, Jie Fan, Greg Elson, Limin Shang, Susana Salgado Pires, Yi Shan Lee, Jesse Guardado, Melanie Scott, and Timothy R Billiar.
• *Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania †Department of Trauma Surgery, University of Heidelberg, Heidelberg, Germany ‡Novimmune SA, Geneva, Switzerland §Glenmark Pharmaceuticals SA, La-Chaux-de-Fonds, Switzerland.
• Shock. 2016 Nov 1; 46 (5): 519-526.

BackgroundAlthough the role of TLR4 in driving inflammation and organ injury after hemorrhagic shock and resuscitation (H/R) is well established, the role of TLR2-another receptor for damage-associated molecular pattern (DAMP) molecules-is not. In this study, we used a combination of TLR2 and wild type (WT) mice treated with anti-TLR2 and anti-TLR4 neutralizing monoclonal antibodies (mAb) to discern the contribution of TLR2 relative to TLR4 to the systemic inflammatory response in murine H/R.Material And MethodsWT mice, TLR2, and WT mice receiving an anti-TLR2 or an anti-TLR4 mAB (given as a pretreatment) were sacrificed at 6 or 20 h post-H/R. Bone marrow TLR2/WT chimeric mice were created to assess the importance of immune and nonimmune cell-associated TLR2.ResultsTLR2 mice subjected to H/R exhibited significantly less liver damage and lower markers of systemic inflammation only at 20 h. Bone marrow chimeric mice using combinations of TLR2 mice and WT mice demonstrated that TLR2 on non-bone marrow derived cells played a dominant role in the differences at 20 h. Interestingly, WT mice treated with anti-TLR2 mAB demonstrated a reduction in organ damage and systemic inflammation at both 6 and 20 h following H/R. A combination of anti-TLR2 mAB and anti-TLR4 mAB showed that both receptors drive IP-10 and KC levels and that there is cooperation for increases in IL-6, MIG, and MCP-1 levels between TLR2 and TLR4.ConclusionThese data also support the conclusion that TLR2 and TLR4 act in concert as important receptors in the host immune response to H/R.

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