Abstract
Chronic psychological stress is a major predisposing factor that worsens sepsis outcomes, yet the neural mechanisms linking stress exposure to immune dysregulation remain poorly understood. Here, using a mouse model of chronic restraint stress (CRS) followed by endotoxemia, we show that prior stress markedly aggravates mortality, systemic inflammation, and immune imbalance during sepsis. Mechanistically, we identify a stress-sensitive medial prefrontal cortex (mPFC)-dorsal motor nucleus of the vagus (DMV) circuit that functions as a central regulator of peripheral neuroimmune homeostasis. Chronic stress is associated with impaired mPFC-DMV circuit function, accompanied by reduced splenic nerve activity, disrupted splenic norepinephrine (NE) and acetylcholine (ACh) signaling, heightened inflammatory responses, and diminished regulatory T cell (Treg) activity. Chemogenetic activation of the mPFC-to-DMV pathway restores splenic autonomic output, normalizes neurotransmitter homeostasis, attenuates systemic inflammation, improves survival, and rescues stress-associated Treg dysfunction. Importantly, chemical sympathectomy with 6-hydroxydopamine (6-OHDA) largely attenuates the protective effects of circuit activation, including its regulation of splenic NE/ACh balance, inflammatory cytokine production, and Treg responses, indicating that intact splenic sympathetic neuroimmune signaling is required for mPFC-DMV-mediated immunomodulation. Furthermore, in vitro experiments reveal that exogenous ACh promotes macrophage-mediated Treg activation through α7 nicotinic acetylcholine receptors (α7nAChRs), providing a cellular mechanism through which autonomic neurotransmitter signaling regulates peripheral immune homeostasis. Together, these findings define a functional cortical-autonomic-immune axis through which chronic stress disrupts neuroimmune homeostasis during sepsis. Our findings further identify autonomic neurotransmitter signaling and α7nAChR-dependent macrophage-Treg communication as key mechanisms linking cortical circuit dysfunction to peripheral immune dysregulation, highlighting cortical-autonomic neuromodulation as a potential therapeutic strategy for stress-associated immune dysfunction in sepsis.