Spices to combat sepsis – Curcumin piperine combination increases survival and modulates immune response in a murine two-hit trauma model

Context: Following trauma Systemic Inflammatory Response Syndrome (SIRS) and its counterpart the Compensatory Anti-inflammatory Response Syndrome (CARS) interact in a very sensitive balance. CD4+ T regulatory cells (CD4+ Tregs) play a crucial role in this interaction and can have a protective effect. We were able to show a reciprocal activation of CD4+ Tregs and platelets early after trauma. With this study we aimed to investigate the immunomodulatory potential of curcumin + piperine (C+P) or ancrod and to clarify their effect on the survival rate in a long-term two-hit trauma model. Methods: C57BL/6N-mice were subjected to standardized burn injury inducing SIRS, followed by sepsis induction via Cecal Ligation and Puncture (CLP) seven days later. Mice treated with C+P or ancrod were compared to control groups. After CLP, animals received no further sepsis treatment. At a maximum follow-up period of 23 days or upon reaching termination criteria, tissue was collected for pathohistological and immunohistochemical evaluation as well as immunological analysis using (phospho-)flow cytometry and multiplex ELISA. Results: Curcumin + piperine treated mice showed a clear survival advantage (p = 0.0097) with systemic alterations in cytokine levels, e.g. for IL-4 (p = 0.0263) and IL-10 (p = 0.0022). Their total organ damage was comparable to Sham-group. C+P also had a significant effect on extracellular T cell activation markers. CD8+ T cells showed lower MHC II (MFI = 1.20) and CD69 (MFI = 2.45) expression in C+P-group compared to Burn/CLP-group (MFI = 1.46; p = 0.0215 and MFI = 3.58; p = 0.0347). In CD4+ T cells the enhancement of extracellular markers CD38 (p = 0.0130) and MHC II (p = 0.0330) proved an increased activity. This was underlined by elevated intracellular signal molecules ZAP-70 (p = 0.0002) and PKC-θ (p = 0.0001) as well as their phosphorylated forms with distinct differences between CD4+ Tregs and nonTregs. (ZAP-70: p = 0.0153; PKC-θ: p = 0.0085). In platelets we found a decreased expression of the activation marker CD62 (p = 0.0229). Conclusion: Curcumin + piperine improves the long-term outcome in a murine two-hit trauma model. It can balance the post-traumatic immune response by its effect on T cells and platelets. CD4+ Tregs seem to be primed for further activation, whereas downregulation of CD8+ T cell and platelet response may reduce proinflammatory signals. This defines curcumin (+ piperine) a promising substance for further investigation.