Splenic nerves NE beta2AR axis exacerbate septic acute kidney injury via modulating neutrophilic immunosuppression

Sepsis is characterized by chronic inflammation and immunosuppression, two immune states that hinder effective infection control and significantly contribute to renal pathological damage. Recent studies have underscored the crucial role of splenic neuroimmune interactions in immune response regulation. However, the precise mechanisms and functions of splenic nerve regulation of splenic immune responses in sepsis-associated acute kidney injury (SA-AKI) remain obscure. Our research suggests that preemptive Splenic Denervation in mice can mitigate sepsis-induced renal injury, while local norepinephrine injection into the spleen exacerbates sepsis-induced kidney damage in the cecal ligation and puncture (CLP) mouse model. Targeted blockade of splenic b2-adrenergic receptor signaling leads to increased survival rates and diminished renal damage in the mice treated with CLP. Subsequent experiments involving local splenic administration of Gr-1 antibodies and myeloid cell-specific conditional knockout of Adrb2 in mice validate that during sepsis, NE/b2-AR signaling can impact splenic neutrophils, fostering the progression of acute sepsis. Mechanistic inquiries reveal that