Spices to Combat Sepsis: Curcumin and Piperine Combination Increases Survival and Modulates Immune Response in a Murine Two-Hit Trauma Model

Abstract

Background: Following trauma, SIRS and CARS interact in a sensitive balance with CD4 + Tregs considered as protective. Previously we showed a reciprocal activation of CD4 + Tregs and platelets early after trauma. Here, we investigated the immunomodulatory potential and survival advantage due to treatment with curcumin + piperine (C + P) or ancrod in a long-term two-hit trauma model.

Methods: C57BL/6N mice were subjected to SIRS by burn injury, followed by sepsis induction via CLP 7 days later. At a maximum follow-up period of 23 days pathohistology, immunohistochemistry, (phospho-)flow cytometry and multiplex Enzyme-linked Immunosorbent Assay were performed.

Results: C + P-treated mice showed a clear survival advantage ( P = 0.0097) with alterations in cytokine levels. Organ damage was similar to Sham group. CD8 + T cells exhibited lower major histocompatibility complex II and CD69 expression in C + P group compared with Burn/CLP group ( P = 0.0215; P = 0.0347). In CD4 + T cells, the enhancement of extracellular markers CD38 ( P = 0.0130) and major histocompatibility complex II ( P = 0.0330) proved an increased activity, underlined by elevated intracellular signal molecules ZAP-70 ( P = 0.0002) and PKC-θ ( P = 0.0001) and their phosphorylated forms, with distinct differences between CD4 + Tregs and non-Tregs (ZAP-70: P = 0.0153; PKC-θ: P = 0.0085). Platelets expressed lower levels of the activation marker CD62 ( P = 0.0229).

Conclusion: C + P improves the long-term outcome in a murine two-hit trauma model by balancing the posttraumatic immune response. CD4 + Tregs seem to be primed for further activation, whereas downregulation of CD8 + T cells and platelets may reduce proinflammatory signals.

Keywords: Burn; CARS; CLP; SIRS; T cells; platelets; sepsis.