Abstract

Sepsis-induced excessive inflammation contributes to mortality, but restricting hyperinflammation in sepsis remains challenging. Here, we identify dipeptidase 2 (DPEP2) as an immunotherapeutic target in sepsis by integrating single-cell and bulk RNA sequencing data from septic patients. In patients with sepsis, peripheral monocytes/macrophages have reduced DPEP2 expression, with DPEP2 levels negatively correlating with inflammation severity, disease progression, and clinical outcomes. In vitro, Dpep2 knockdown enhances macrophage-mediated inflammation, while in septic mice in vivo, macrophage-specific Dpep2 loss decreases survival by exacerbating inflammation and organ damage. Mechanistically, sepsis-induced EGR1 represses Dpep2 transcription, leading to reduced DPEP2-mediated enzymatic cleavage of leukotriene D4 (LTD4). Increased LTD4 redirects the metabolic flux toward prostaglandin E2 overproduction, amplifying NF-κB activation and lipopolysaccharide-induced inflammatory cytokine production. Lastly, lipid nanoparticle (LNP)-mediated delivery of Dpep2 mRNA expression to monocytes/macrophages mitigates inflammation and organ damage in septic mice. Our findings thus suggest a protective function for DPEP2 in sepsis-induced hyperinflammation via immunometabolic regulation, and also present LNP-mediated Dpep2 mRNA delivery as a potential therapy for septic hyperinflammation.