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

Abstract

Abstract 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.