A neuroimmune pathway drives bacterial infection

Area of Science:

• Neuroimmunology
• Immunometabolism
• Sepsis Pathophysiology

Background:

• Sepsis poses a significant public health threat, with its neuroimmune underpinnings poorly understood.
• ACOD1 (Aconitate decarboxylase 1) is an immunometabolism regulator activated during bacterial infection.
• Neurotransmitter roles in sepsis-induced immune responses remain largely unexplored.

Purpose of the Study:

• To investigate neurotransmitter modulation of ACOD1 expression in innate immune cells.
• To elucidate the neuroimmune mechanisms linking dopamine signaling to sepsis pathophysiology.
• To evaluate the therapeutic potential of targeting the dopamine-ACOD1 axis in sepsis.

Main Methods:

• Screening of neurotransmitters for their effect on lipopolysaccharide (LPS)-induced ACOD1 expression.
• Investigating the molecular interactions between dopamine receptor D2 (DRD2), Toll-like receptor 4 (TLR4), and downstream signaling pathways (MAPK3, CREB1).
• Assessing the impact of dopamine agonists (pramipexole) and antagonists (aripiprazole) on sepsis mortality in mouse models and analyzing patient data.

Main Results:

• Dopamine was identified as a potent inhibitor of LPS-induced ACOD1 expression in innate immune cells.
• DRD2 forms a complex with TLR4, inhibiting TLR4-MYD88 interaction and subsequently ACOD1 transcription.
• Enhanced ACOD1 expression promotes CD274/PD-L1 production, contributing to sepsis-induced immunosuppression. Pramipexole mitigated sepsis lethality, while aripiprazole exacerbated it.
• Dopamine-ACOD1 axis dysregulation correlated with sepsis severity in patients.

Conclusions:

• Dopamine signaling, through DRD2, negatively regulates ACOD1 expression and subsequent immunosuppression in sepsis.
• The dopamine-ACOD1 axis represents a critical neuroimmune pathway in sepsis.
• Targeting this axis with dopamine agonists may offer a novel therapeutic strategy for sepsis management.