Abstract
Sepsis, caused by an unbalanced host response to infection, remains a global health burden. The dysregulation between pro-inflammatory and anti-inflammatory responses is a primary driver of immune imbalance. As a central player in adaptive immunity, CD4(+) T cells are crucial for maintaining this balance during sepsis by differentiating into various effector T cell subsets. Thus, elucidating the underlying mechanisms within the inflammatory and anti-inflammatory imbalance in CD4(+) T cell subsets during sepsis is of great value. We first identified the proviral integration site for Moloney murine leukemia virus 1 (PIM1) as a significantly upregulated gene in CD4(+) T cells from sepsis patients by conducting a comprehensive transcriptome meta-analysis. The expression of PIM1 was significantly elevated on CD4(+) T cells from sepsis patients and was correlated with both SOFA and APACHE II scores. Moreover, we found that PIM1 promoted the differentiation of CD4(+)IFN-γ(+) Th1 and CD4(+)IL-17A(+) Th17 subsets while inhibiting the differentiation of CD25(+)FoxP3(+) Tregs. Additionally, upon inhibiting PIM1 kinase activity in CD4(+) T cells, RNA sequencing analysis revealed that the cholesterol metabolism gene, ATP-binding cassette transporter G1 (ABCG1), exhibited significant upregulation. More importantly, we found that the intracellular cholesterol content was decreased in CD4(+) T cells after inhibiting the PIM1 kinase activity or knocking down PIM1. The portion of CD4(+)IFN-γ(+) Th1 and CD4(+)IL-17A(+) Th17 cells was recovered, and the CD4(+)CD25(+)FoxP3(+) Tregs decreased after cholesterol supplementation to CD4(+) T cells. These findings indicated that PIM1 may regulate the balance of Th1, Th17, and Treg subsets in a cholesterol-dependent manner in sepsis.IMPORTANCEThis study aims to elucidate the mechanism of the inflammatory and anti-inflammatory imbalance of CD4(+) T cell subsets during sepsis. Our study provides evidence that PIM1 serves as a crucial regulator of sepsis-induced inflammation and elucidates that PIM1 participates in regulating the imbalance of Th1, Th17, and Treg subsets, further promoting inflammatory and anti-inflammatory imbalance in sepsis. Additionally, the cholesterol metabolism, potentially mediated by ABCG1, is implicated in PIM1's regulatory effect on the Th1, Th17, and Treg imbalance. Our study provides novel insights into the inflammatory imbalance during sepsis, which could facilitate the development of therapeutic strategies aimed at modulating the immune-inflammatory cascade in this condition.