Splenic nerves NE-β2AR axis exacerbate septic acute kidney injury via modulating neutrophilic immunosuppression [RNA-seq]

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 β2-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/β2-AR signaling can impact splenic neutrophils, fostering the progression of acute sepsis. Mechanistic inquiries reveal that splenic Adrb2 signaling boosts neutrophil PGE2 signaling through the cAMP pathway, promoting Th1 activation, diminishing local bacterial infections, and ameliorating SA-AKI. Furthermore, Blocking ADRB2 or PGE2 synthesizing signal significantly modulates the immunosuppression effect of neutrophils, promoting anti-bacterial Th1 immune response. These studies elucidate the role of splenic NE-ADRB2 signaling in regulating neutrophil immunosuppressive functions, thereby influencing the advancement of sepsis and renal tissue damage.