Tlr2 on Bone Marrow and Non-Bone Marrow Derived Cells Regulates Inflammation and Organ Injury in Cooperation with Tlr4 During Resuscitated Hemorrhagic Shock

Abstract

Background Although 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 Methods WT mice, TLR2−/− and WT mice receiving an anti-TLR2 or an anti-TLR4 mAB (given as a pre-treatment) were sacrificed at 6 or 20 hr post-H/R. Bone marrow TLR2/WT chimeric mice were created to assess the importance of immune and non-immune cell-associated TLR2. Results TLR2−/− mice subjected to H/R exhibited significantly less liver damage and lower markers of systemic inflammation only at 20 hr. 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 hr. Interestingly, WT mice treated with anti-TLR2 mAB demonstrated a reduction in organ damage and systemic inflammation at both 6 and 20 hrs 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. Conclusion These data also support the conclusion that TLR2 and TLR4 act in concert as important receptors in the host immune response to H/R.

Toll-Like Receptor 4 on both Myeloid Cells and Dendritic Cells Is Required for Systemic Inflammation and Organ Damage after Hemorrhagic Shock with Tissue Trauma in Mice

“…Cryostat sections of the tissues (6 µm) were stained with hematoxylin and eosin (H&E) to evaluate histopathologic cumulative changes among treatment groups. Images of five randomly selected fields were acquired using an Olympus Provis light microscope (Malvern, NY, USA) with 200× magnification ( 37 ).…”

Innate immunity and immunotherapy for hemorrhagic shock

“…A recent finding has shown that anti-IL-5 antibody, IL-33, or ILC2 deletion, significantly increased IL-5 expression in neutrophils and decreased lung injury scores at 6 h in the HS-induced mice injury model ( 77 ). DAMPs can activate systemic inflammation and organ injury in HS through binding to TLR2 on immune cells ( 78 ). Similarly, anti-TLR2 monoclonal antibody or TLR2 -/- mice exhibited significantly less liver damage, and lower NF-κB and inflammatory cell infiltrate in HS at 20 h ( 78 ).…”

Attenuation of hemorrhage-associated lung injury by adjuvant treatment with C23, an oligopeptide derived from cold-inducible RNA-binding protein

“…HS-associated lung injury is generally thought to develop in part due to reperfusion, which can cause cellular stress and the release of damage-associated molecular pattern (DAMP) molecules and inflammatory mediators, leading to leukocyte and vascular endothelial cell (EC) activation, increased capillary permeability, neutrophil infiltration, and tissue injury [12-15]. Cold-inducible RNA-binding protein (CIRP) is a highly conserved nuclear protein upregulated by hypoxia and mild hypothermia [16, 17].…”