The autophagy-inhibitory tissue hormone DBI/ACBP contributes to the pathogenesis of multiple organ dysfunction...

Systemic microbial infection leading to septic shock with multiple organ dysfunction syndrome (MODS) is a major cause of mortality and represents a substantial unmet medical need. We recently observed that, compared with uninfected controls, patients with septic shock exhibit significantly elevated circulating concentrations of the tissue hormone acyl-CoA binding protein (ACBP), encoded by the diazepam binding inhibitor (DBI) gene, a potent inhibitor of autophagy. Increased plasma DBI/ACBP levels correlated with disease severity and poor clinical outcome. Similarly, DBI/ACBP concentrations were elevated in three distinct mouse models of septic shock induced by (i) bacterial lipopolysaccharide injection, (ii) inoculation with monomicrobial Escherichia coli or (iii) polymicrobial sepsis following cecal ligation and puncture. In all three models, neutralization of DBI/ACBP using specific monoclonal antibodies significantly reduced mortality. Comprehensive behavioral, cardiac, pulmonary, hepatic, renal and splenic phenotyping further demonstrated that DBI/ACBP neutralization alleviated all hallmarks of MODS, including impaired thermoregulation, lethargy and organ failure affecting the heart, lungs, liver and kidneys. Multi-omics analyses, including bulk transcriptomics, metabolomics and high-dimensional immunophenotyping, revealed that DBI/ACBP neutralization attenuated sepsis-associated alterations in gene expression, metabolism and myeloid cell infiltration across major organs. Mechanistically, DBI/ACBP inhibition enhanced organ resistance to lipopolysaccharide-induced sterile inflammation while simultaneously promoting bacterial clearance by macrophages and granulocytes both in vivo and in vitro in models of monomicrobial and polymicrobial sepsis. Collectively, these findings identify DBI/ACBP as a pathogenic mediator of sepsis, consistent with its previously described anti-autophagic, immunosuppressive, pro-inflammatory and pro-senescent properties.