The activation of glial cells in the medulla visceral zone impairs synaptic plasticity and promotes inflammation and immune disorders in sepsis.

Abstract

Objective: Sepsis elicits neuroinflammation in the medullary visceral zone (MVZ), which disrupts the cholinergic anti-inflammatory pathway (CAP). However, the underlying mechanisms and translational therapeutic potential remain poorly defined.

Methods: Adult male Sprague-Dawley rats received either intracerebroventricular lipopolysaccharide (LPS; 25 μg/25 μL) to induce MVZ neuroinflammation model rats, or intraperitoneal LPS (6 mg/kg) to establish polymicrobial sepsis model rats. Anti-inflammation groups were involved with minocycline sucrose solution (120 mg/L) which was administered by drinking for 4 days prior to LPS challenge. CAP transection groups were undergone right cervical vagotomy 7 days before anti-inflammation interventions. Murine sepsis score (MSS), mortality rates, heart rate variability (HRV), cytokine levels in blood and medulla, systemic immunity level, and the expression levels of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (IBA-1), CD22, tumor necrosis factor-α (TNF-α), Munc13-1, Synaptophysin (SYN), and postsynaptic density protein 95 (PSD-95) in the MVZ were measured and analyzed.

Results: Both sepsis and MVZ neuroinflammation model rats showed significantly increased mortality and MSS scores, depressed HRV parameters, and upregulated expressions of GFAP, IBA-1, CD22, and TNF-α, with downregulated expressions of Munc13-1, SYN, and PSD-95 in the MVZ. Synaptic structural damage including reduced synaptic vesicles, decreased RT1.D expression on lymphocytes, increased percentages of Th17 and Treg lymphocytes, and increased serum levels of TNF-α, IL-10, and INF-γ were observed. Anti-inflammatory intervention reversed these changes in both model rats, whereas CAP transection partially abolished the anti-inflammatory benefits, confirming CAP dependence.

Conclusions: Sepsis-induced MVZ neuroinflammation dismantles synaptic integrity and CAP modulation, which intensifies peripheral cytokine storm. Early central anti-inflammation repairs MVZ synaptic plasticity and reinstates vagal immunomodulation, which may provide a translational strategy to limit septic escalation.