Abstract
Sepsis survivors face a heightened risk of secondary infections following discharge, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of endothelial inflammatory memory, wherein inflammatory exposure induces durable chromatin remodeling in endothelial cells (ECs), priming them for exaggerated responses to a subsequent infection. Utilizing a clinically relevant two-hit mouse model, cecal ligation and puncture (CLP) followed by mild Streptococcus pneumoniae (Sp) infection in CLP survivors, we reveal transcriptional activation in endothelial cells (ECs) following secondary infection, marked by significantly elevated expression of proinflammatory cytokines, adhesion molecules, complement factors, and interferon-stimulated genes. Genome-wide ATAC-seq revealed that a subset of inflammatory gene loci retained increased chromatin accessibility even after cytokine withdrawal, demonstrating stable epigenetic remodeling consistent with transcriptional priming and inflammatory memory. In vitro, we uncovered a critical role for the activator protein-1 transcription factor JunB in mediating this epigenetic remodeling. JunB knockdown attenuated chromatin accessibility after an initial IL-6 challenge and subsequent transcriptional amplification upon a secondary LPS challenge, pinpointing JunB-driven chromatin modifications as central to endothelial reprogramming. Our findings offer mechanistic insights into how transient inflammation creates lasting epigenetic states within the endothelium, highlighting JunB as a potential therapeutic target to mitigate chronic endothelial dysfunction and increased susceptibility to secondary infections postsepsis.NEW & NOTEWORTHY We uncover that endothelial cells retain a form of inflammatory memory, driven by chromatin remodeling and sustained JunB activity. Using two-hit models in mice and human endothelial cells, we show that an initial inflammatory exposure primes the endothelium for exaggerated responses to future inflammation. This discovery reveals a new mechanism of chronic endothelial dysfunction and identifies JunB as a potential therapeutic target in postsepsis care.