Bortezomib promotes neutrophil-mediated bacterial clearance in sepsis by inhibiting plasmablast activation.

BACKGROUND AND PURPOSE: Sepsis induces immunosuppression, contributing to high mortality. Plasmablasts, including an IL-10-producing regulatory subset, expand during sepsis to exert immunosuppressive functions. This study examined how depleting plasmablasts can improve the prognosis of sepsis, and investigated the underlying mechanisms by focusing on neutrophil function.

EXPERIMENTAL APPROACH: Plasmablasts were depleted in vivo in CD138-diphtheria toxin receptor (DTR) transgenic mice subjected to caecal ligation and puncture (CLP)-induced sepsis. The effects of plasmablast depletion on animal survival, bacterial load, inflammatory mediators, and neutrophil number and function were assessed. The proteasome inhibitor bortezomib (BTZ) was evaluated for its ability to suppress plasmablasts, and its therapeutic efficacy in wild-type mice with sepsis.

KEY

RESULTS

Plasmablast depletion in CD138-DTR mice was associated with an increase in the number and antibacterial function of neutrophils, including increased production of reactive oxygen species (ROS) and phagocytic capacity. In vitro co-culture experiments demonstrated that plasmablasts suppressed neutrophil activity, an effect mediated by adenosine and IL-10 signalling. Treatment of wildtype septic mice with BTZ effectively reduced plasmablast abundance and CD39 expression. BTZ 0.05 mg·kg-1 mirrored the protective effects of genetic ablation, improved survival, reduced bacterial burden and inflammation and improved neutrophil-mediated bacterial clearance. At high concentrations, BTZ worsened outcomes and is an unlikely magic bullet for sepsis without stringent dosing controls.

CONCLUSION AND IMPLICATIONS: Plasmablasts contribute to sepsis immunosuppression by affecting 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.