Bortezomib Promotes Neutrophil-Mediated Bacterial Clearance in Sepsis by Inhibiting Plasmablast Activation

Background and Purpose: Sepsis induces immunosuppression, contributing to high mortality. Plasmablasts, a regulatory B cell subset that expands during sepsis, are known to suppress immune function, but the consequences of their specific removal on sepsis outcome remain unclear. This study aimed to determine whether depleting plasmablasts could improve sepsis prognosis and to investigate the underlying mechanisms, with a focus on neutrophil function. Experimental Approach: We utilized a genetic approach to selectively deplete plasmablasts in vivo by using CD138-diphtheria toxin receptor (DTR) transgenic mice subjected to cecal ligation and puncture (CLP)-induced sepsis. The effects of plasmablast depletion on survival, bacterial load, inflammatory mediators, and neutrophil number and function were assessed. Furthermore, the proteasome inhibitor bortezomib was evaluated for its ability to suppress plasmablasts and its therapeutic efficacy in wild-type mice with sepsis. Key Results: Depletion of plasmablasts in CD138-DTR mice significantly improved survival and reduced bacterial load in the peritoneal cavity. This was associated with a marked increase in the number and antibacterial function of neutrophils, including enhanced reactive oxygen species production and phagocytic capacity. In vitro co-culture experiments demonstrated that plasmablasts directly suppressed neutrophil activity, an effect mediated via adenosine and IL-10 signaling. Treatment of wild-type septic mice with bortezomib effectively reduced plasmablast abundance and CD39 expression, and a specific dosing regimen (0.05 mg/kg) mirrored the protective effects of genetic ablation, improving survival, reducing bacterial burden and inflammation, and enhancing neutrophil-mediated bacterial clearance. Conclusion and Implications: Our findings establish plasmablasts as a critical contributor to sepsis immunosuppression by directly impairing neutrophil function. The clinically available drug bortezomib can target this population, positioning plasmablast inhibition as a novel and translatable therapeutic strategy to improve bacterial clearance and survival in sepsis.