A neuroimmune pathway drives bacterial infection

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-05-02 DOI:10.1126/sciadv.adr2226

Nian Wang, Jiao Liu, Runliu Wu, Feng Chen, Ruoxi Zhang, Chunhua Yu, Herbert Zeh, Xianzhong Xiao, Haichao Wang, Timothy R. Billiar, Ling Zeng, Jianxin Jiang, Daolin Tang, Rui Kang

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Abstract

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.

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神经免疫途径驱动细菌感染

病原体引起的脓毒性死亡是一项重大的公共卫生挑战，其神经免疫机制在很大程度上尚未被探索。我们的研究探讨了ACOD1表达的神经递质调节，ACOD1是细菌脂多糖（LPS）激活的免疫代谢调节剂。筛选神经递质发现多巴胺是先天免疫细胞中lps诱导的ACOD1表达的有效抑制剂。从机制上讲，DRD2与TLR4形成复合物，启动mapk3依赖性CREB1磷酸化和随后的ACOD1转录。相反，多巴胺通过DRD2破坏TLR4-MYD88相互作用，而不影响lps诱导的TLR4-MD2-CD14复合物的形成。ACOD1表达增强诱导CD274/PD-L1的产生，独立于衣康酸，在脓毒症中加速炎症相关的免疫抑制。延迟给药普拉克索，一种多巴胺激动剂，减轻细菌性败血症小鼠模型的致死率。相反，多巴胺拮抗剂阿立哌唑会加重败血症的死亡率。多巴胺- acod1轴的失调与患者脓毒症的严重程度相关，表明调节这一神经免疫途径的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.