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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]

The Th17/ Treg axis is a crucial regulator of anti-inflammatory and proinflammatory pathways that play fundamental roles in cancer and autoimmune diseases. The alteration of the Th17/Tregs axis is highly significant for developing novel therapeutic approaches. Th17 and Treg cells share a large portion of their transcriptome, albeit with distinct functions. The mechanisms governing the bifurcation of Th17 /Treg axis differentiation from naïve T cells are not yet understood. This study aims to identify the differentially expressed genes (DEGs) and gene-enriched pathways that contribute to the distinction between these closely aligned phenotypes. We analyzed RNA sequencing data of CD4+ T cells differentiated in vitro into Th0, Th17, and Tregs phenotypes and built gene enrichment networks. We studied the network rewiring of Th17 and Tregs from Th0 cells. In addition to common pathways and genes that are equally expressed between these two distinct phenotypes, we identified key genes and pathways that contribute to their distinctiveness. For example, the Keap1 gene and several of its interactors such as MCC1 were upregulated in Tregs indicating that Tregs possess mechanisms that prevent the over-activation of antioxidants pathways. Tregs also possess several genes that are involved in the hydrolysis of ATP to ADP as RAB37, ATP1A2, ATP1B, and PDE2A to ensure Treg anti-inflammatory capabilities. Additionally, one of the pathways that ensure Tregs differentiation and function seems to point toward an insulin role mediated by APOL9B and GOLM. Taken together our findings shed light on various essential regulators of the Th17/Treg axis and pave the way for treatment strategies that selectively target one phenotype while sparing the other. [ABSTRACT FROM AUTHOR]