The splenic norepinephrine-β2-adrenergic receptor axis aggravates sepsis-associated acute kidney injury via neutrophil-mediated immunosuppression.

Abstract

Sepsis-associated acute kidney injury (SA-AKI) is frequently complicated by immune paralysis and kidney infection. Despite the spleen's critical immunological role, the neural mechanisms regulating the splenic immune responses during SA-AKI remain unclear. To examine this, we used splenic denervation, continuous intrasplenic infusion, single-cell sequencing and neutrophil-specific β_2-adrenergic receptor Adrb2 knockout mice to define the role of the splenic norepinephrine-β2-adrenergic receptor (NE/β2-AR) axis in SA-AKI. Our findings indicate that pre-emptive splenic denervation in mice mitigates sepsis-induced kidney injury, whereas local intrasplenic norepinephrine infusion exacerbates kidney damage in a cecal ligation/puncture (CLP) mouse model. Targeted blockade of splenic β2-adrenergic receptor (β2-AR) signaling enhances survival and attenuates kidney damage in CLP mice. Local splenic depletion of neutrophil and neutrophil-specific conditional knockout of Adrb2 demonstrate that NE/β2-AR signaling influences splenic neutrophils, thereby driving the progression of acute sepsis. Mechanistic investigations reveal that splenic NE/β2-AR signaling enhances neutrophil prostaglandin E₂ synthesis via the cAMP-response element binding protein pathway, thereby suppressing T helper 1 cell activation, increasing local bacterial infections, and aggravating SA-AKI. These findings clarify the role of splenic NE/β2-AR signaling in modulating neutrophil-mediated immunosuppression, thereby driving sepsis progression and aggravating kidney damage.