A neuroimmune pathway drives bacterial infection.

Summary

This mechanistic study identifies a dopamine–DRD2–TLR4 signaling complex that modulates ACOD1 transcription and drives PD-L1–mediated immunosuppression in sepsis. Dopamine agonism (pramipexole) improved survival in murine sepsis when given late, whereas a dopamine antagonist worsened mortality; dysregulation of this axis correlated with patient severity.

Key Findings

• Dopamine via DRD2 inhibits LPS-induced ACOD1 expression in innate immune cells.
• DRD2 forms a complex with TLR4, triggering MAPK3-dependent CREB1 phosphorylation to drive ACOD1 transcription.
• Dopamine disrupts TLR4–MYD88 interaction without affecting TLR4–MD2–CD14 complex formation.
• Upregulated ACOD1 induces PD-L1 production independently of itaconate, promoting immunosuppression in sepsis.
• Delayed pramipexole reduced lethality in murine bacterial sepsis, while aripiprazole increased mortality.
• Dopamine–ACOD1 axis dysregulation correlates with sepsis severity in patients.

Clinical Implications

Dopamine agonists may merit evaluation as adjuncts in bacterial sepsis, while caution with dopamine antagonists could be warranted in septic patients. Biomarkers along the DRD2–TLR4–ACOD1–PD-L1 axis could stratify patients for immunomodulatory therapies.

Limitations

• Translational findings are preclinical; no human interventional data
• Human cohort size and confounders for the correlation analysis are not specified

Future Directions

Prospective biomarker studies of the DRD2–TLR4–ACOD1–PD-L1 axis and early-phase trials testing dopaminergic modulators as adjunctive therapy in sepsis.