Acod1 mediates anti-inflammatory Treg function in sepsis.

Sepsis is a serious, potentially fatal disease caused by the body's reaction to microbial invasions by bacteria, viruses, and fungi. Current research shows that the process of fighting sepsis passes through two phases. The first phase is a cytokine storm, and the second phase involves a cycle of pro-inflammatory and anti-inflammatory responses led by Regulatory CD4+ T-cells (CD4+ Tregs). Various immunomodulatory therapies have been proposed to break the cycle of pro- and anti-inflammatory reactions to sepsis. However, clinical trials are yet to show any promising results, indicating the need for further research into the mechanisms behind Treg dysfunction. We used next-generation sequencing (NGS) analysis of five datasets comprising of bulk RNA-seq and single-cell RNA-seq data to explore our research question. Our results identified Acod1 (Aconitate Decarboxylase 1) as a primary mediator of Treg suppression of immune cells as well as various metabolic pathways regulated by IL4 and IL10. scRNA-seq analysis showed that Acod1 and FoxP3 were localised in the same Treg-like cells. Further evidence from our study further suggests a mutual positive regulation loop between Acod1 and FoxP3 in sepsis. Additionally, CD36 was identified as a downstream target of Acod1. CD36 is a known metabolite regulator in Tregs, where it functions as a transporter of long fatty chains (LCFA) and is regulated by IL4 and IL10. Taken together, our results indicate that the metabolic CD36/Acod1 axis could be responsible for the continuous activation of Treg in sepsis. Thus, targeting this axis could prove valuable in improving the sepsis prognosis. [ABSTRACT FROM AUTHOR]