D 4 -CHIP REVEALS IMPAIRED T-CELL FUNCTION IN SEPSIS: INSIGHTS FROM PLASMA MICROENVIRONMENT ANALYSIS AND MITOCHONDRIAL-TARGETED THERAPY.

Abstract

Abstract: Background: Sepsis, a systemic inflammation syndrome initiated by infection, poses significant challenges due to its intricate pathophysiology. T cells play a crucial role in combating infections during sepsis. Despite previous observations indicating T-cell dysfunction in sepsis, reliable in vitro detection methods were lacking, and the factors influencing these impairments remained unclear. Methods: We developed a novel method using the D 4 -Chip to assess sepsis T-cell migration function. This microfluidic platform enabled precise analysis of migration function under controlled conditions. Additionally, We explored the impact of the plasma microenvironment on T-cell behavior, along with the redox environment in sepsis, and assessed the potential efficacy of Mitoquinone mesylate (MitoQ), a mitochondrial-targeted drug. Results: Our findings revealed impaired migration function in sepsis T cells compared to healthy controls. Interestingly, sepsis plasma enhanced the migration of healthy T cells, yet incubation with healthy plasma did not fully restore migration impairments in sepsis T cells. Subsequent investigations uncovered a significant increase in NADH/NAD+ levels in sepsis T cells, with healthy T cells exposed to various sepsis plasma conditions also showing elevated NADH/NAD+ levels. Importantly, MitoQ normalized abnormal intracellular NADH/NAD+ levels and enhanced the migration ability of T cells. Conclusions: Short-term incubation with sepsis plasma does not directly inhibit T-cell migration but instead affects T-cell function by disrupting the intracellular redox environment. Improving the intracellular redox environment of sepsis patients contributes to restoring impaired migration and proliferation, with MitoQ demonstrating therapeutic potential.