A neuroimmune pathway drives bacterial infection
Pathogen-induced septic death presents a substantial public health challenge, with its neuroimmune mechanisms largely unexplored. Our study investigates neurotransmitter modulation of ACOD1 expression, a regulator of immunometabolism activated by bacterial lipopolysaccharide (LPS). Screening neurotransmitters identifies dopamine as a potent inhibitor of LPS-induced ACOD1 expression in innate immune cells. Mechanistically, DRD2 forms a complex with TLR4, initiating MAPK3-dependent CREB1 phosphorylation and subsequent ACOD1 transcription. Conversely, dopamine disrupts TLR4-MYD88 interaction via DRD2 without affecting the formation of the LPS-induced TLR4-MD2-CD14 complex. Enhanced ACOD1 expression induces CD274/PD-L1 production independently of itaconate, precipitating inflammation-associated immunosuppression in sepsis. Delayed administration of pramipexole, a dopamine agonist, mitigates lethality in bacterial sepsis mouse models. Conversely, the dopamine antagonist aripiprazole exacerbates sepsis mortality. Dysregulation of the dopamine-ACOD1 axis correlates with sepsis severity in patients, indicating a potential therapeutic target for modulating this neuroimmune pathway.
Authors
- Chunhua Yu (ORCID: https://orcid.org/0000-0002-4325-6634)
- Jiao Liu (ORCID: https://orcid.org/0000-0003-1708-0409)
- Ling Zeng (ORCID: https://orcid.org/0000-0002-9640-9083)
- Xianzhong Xiao (ORCID: https://orcid.org/0000-0001-6706-8665)
- Ruoxi Zhang (ORCID: https://orcid.org/0000-0003-2538-1877)
- Daolin Tang (ORCID: https://orcid.org/0000-0002-1903-6180)
- Timothy R. Billiar (ORCID: https://orcid.org/0000-0002-2949-0811)
- Herbert J. Zeh (ORCID: https://orcid.org/0000-0003-2017-1934)
- Rui Kang (ORCID: https://orcid.org/0000-0003-2725-1574)
- Feng Chen (ORCID: https://orcid.org/0000-0003-0013-479X)
- Haichao Wang (ORCID: https://orcid.org/0000-0002-0211-9000)
- Nian Wang (ORCID: https://orcid.org/0000-0002-8303-0365)
- Jianxin Jiang (ORCID: https://orcid.org/0000-0003-0907-5976)
- Runliu Wu (ORCID: https://orcid.org/0000-0002-6175-8646)
Institutions
- Feinstein Institute for Medical Research (US)
- Central South University (CN)
- University of Pittsburgh (US)
- North Shore University Hospital (US)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- Daping Hospital (CN)
- Southwestern Medical Center (US)
- State Key Laboratory of Respiratory Disease (CN)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1126/sciadv.adr2226
- Citations
- 8
- Primary Topic
- Intensive Care Unit Cognitive Disorders
- Type
- article
- Field-Weighted Citation Impact
- 12.36