The Neuroimmune Axis in Sepsis: From Pathophysiological Circuits to Precision Neuromodulation

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response, is characterized by a dynamic progression from hyperinflammation to immunosuppression. Its persistently high mortality underscores the limitations of therapies focused solely on immune homeostasis. This review advocates a paradigm shift that positions the nervous system as a central orchestrator of host defense through a hierarchical neuroimmune axis. This axis comprises three interconnected tiers: (1) peripheral effector pathways-the cholinergic anti-inflammatory pathway and the sympathetic-adrenal-medullary axis; (2) central integrative hubs in the brainstem (eg, nucleus tractus solitarius) and limbic system; and (3) molecular translators that convert neural signals into cellular immune responses. In sepsis, maladaptive plasticity within these circuits leads to a pathological "uncoupling" of immune sensing from neural control, driving organ dysfunction and perpetuating both runaway inflammation and subsequent immunosuppression. We critically evaluate emerging neuromodulation strategies-including bioelectronic vagus nerve stimulation, splenic focused ultrasound, precise electroacupuncture, and receptor-specific pharmacology-with careful distinction between established mechanistic evidence, preclinical findings, and early-stage clinical data. The future direction lies in precision neuromodulation, an evolving concept encompassing closed-loop systems responsive to dynamic biomarkers, chronotherapy, and targeted nanomedicine, though these approaches require substantial technical and clinical validation. This framework charts a roadmap for evolving sepsis management from supportive care toward proactive modulation of endogenous regulatory networks, while emphasizing that further mechanistic studies, biomarker validation, and well-designed clinical trials are essential prerequisites for clinical translation.