Medial Prefrontal Cortex Modulation of the Peripheral Immune Response in Sepsis Via the Autonomic Nervous System.

Authors

Weiyan Zhang, Qian Zhai, Xiawei Hu, Hui Ye, Weijue Li, Mei Guo, Shengwen Song, Hanbin Wang, Yang Wang, Jiali Mao, Yan Zhang, Kai Zhang, Dixian Wang, Baoli Cheng, Jing-Wei Zhao, Xiangming Fang

Published in

Anesthesia and analgesia. Sep 03, 2026. Epub Sep 03, 2026.

Abstract

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection, in which neuroimmune dysfunction plays a central role. The medial prefrontal cortex (mPFC) is involved in autonomic and immune regulation. However, its role in modulating peripheral immune responses during sepsis remains unclear. This study investigated whether glutamatergic neurons in the mPFC regulate systemic inflammation and organ injury during sepsis via autonomic pathways and adrenergic signaling.
Glutamatergic neurons in the mPFC were selectively manipulated using optogenetic activation or chemogenetic inhibition. Mice were assigned to four main groups: ChR2 (optogenetic activation), mCherry (optogenetic control), hM4Di (chemogenetic inhibition), and EGFP (chemogenetic control). Sepsis was then induced by intraperitoneal injection of Escherichia coli or by cecal ligation and puncture. Serum and splenic cytokines were quantified by enzyme-linked immunosorbent assay (ELISA), organ injury was assessed histologically, and splenic immune cell populations and macrophage polarization were analyzed by flow cytometry. Left cervical vagotomy (LcVGX), β2-adrenergic receptor (ADRB2) antagonism (ICI-118,551), and splenic denervation via 6-hydroxydopamine (6-OHDA) were applied to explore underlying mechanisms.
Sepsis significantly activated mPFC neurons. Optogenetic activation of mPFC glutamatergic neurons reduced proinflammatory cytokine levels and attenuated liver, kidney, and lung injury, whereas chemogenetic inhibition exacerbated systemic inflammation and organ damage. Mechanistically, activation of mPFC neurons promoted macrophage polarization toward the M2 phenotype, whereas inhibition shifted polarization toward the M1 phenotype. LcVGX abolished the anti-inflammatory effects of mPFC activation (percentage of M2 macrophages: ChR2-sham vs mCherry-sham, mean ± SEM 19.4 ± 0.87% vs 14.4 ± 1.15%, P = .023; ChR2-LcVGX vs mCherry-LcVGX, mean ± SEM 14.0 ± 0.89% vs 14.2 ± 1.33%, P > .999; n = 5/group), indicating vagal dependence. Additionally, chemogenetic inhibition increased ADRB2 expression in the spleen, and ADRB2 blockade or splenic denervation reversed the proinflammatory macrophage polarization (percentage of M1 macrophages: hM4Di-saline vs EGFP-saline, mean ± SEM 30.8 ± 1.71% vs 23.0 ± 1.06%, P = .030; hM4Di-ICI-118,551 vs EGFP-ICI-118,551, mean ± SEM 20.9 ± 2.04% vs 21.6 ± 2.14%, P = .992; hM4Di-6-OHDA vs EGFP-6-OHDA, mean ± SEM 26.3 ± 3.00% vs 26.2 ± 2.34%, P > .999; n = 4/group).
Glutamatergic neurons in the mPFC play a critical role in regulating peripheral immune responses during sepsis. The mPFC influences macrophage polarization, systemic inflammation, and organ injury via autonomic pathways involving the vagus and splenic nerves and ADRB2-dependent signaling. Targeting mPFC-mediated neuroimmune pathways may represent a potential therapeutic strategy for sepsis.

PMID:
42690920
Bibliographic data and abstract were imported from PubMed on 04 Sep 2026.

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