An mPFC–DMV cortical–autonomic–immune axis governs stress-induced immune dysregulation in sepsis

Abstract Chronic psychological stress is a major predisposing factor that worsens sepsis outcomes, yet the central neural mechanisms linking stress exposure to immune dysregulation remain poorly defined. Here, using a mouse model of chronic restraint stress followed by endotoxemia, we show that prior stress markedly worsens survival outcomes, amplifies systemic inflammation, and disrupts immune homeostasis during sepsis. We identify a stress-sensitive cortical–brainstem circuit in which dysfunction of the medial prefrontal cortex (mPFC) alters autonomic signaling through the dorsal motor nucleus of the vagus (DMV). In vivo splenic neuroelectrophysiological recordings and neurotransmitter profiling reveal pronounced dysregulation of splenic nerve activity and norepinephrine/acetylcholine balance in stress-primed sepsis. Notably, chemogenetic activation of the mPFC-to-DMV circuit normalizes splenic autonomic output and neurotransmitter dynamics, accompanied by attenuation of inflammatory responses and associated with improved survival. Stress exposure is further associated with altered splenic T cell polarization, including impaired regulatory T cell responses, which are partially restored following mPFC–DMV circuit activation. Together, these findings identify a functional cortical–autonomic gate linking stress exposure to neuroimmune dysregulation in sepsis and highlight cortical neuromodulation as a potential strategy to improve outcomes in stress-primed sepsis.