Gut microbiota-derived histamine exacerbates psoriasis by promoting γδT17 cell differentiation via the Hrh1/Wnt Axis

IF 4.7 2区 医学 Q2 IMMUNOLOGY
Waiming Cheng , Meihong He , Elfira Jurat , Luoyi Jin , Shunchang Luo , Zerong Guan , Yingying Zeng , Xianghong Wang , Jianlei Hao , Xin Tang , Haiyan Zhu , Zhinan Yin , Hengwen Yang
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引用次数: 0

Abstract

Psoriasis is associated with gut microbiota dysbiosis and aberrantly elevated histamine levels, yet the pathological role of microbiota-derived histamine remains unclear. In this study, colonization of mice with histamine-producing engineered E. coli (BL21_pET-17b_hdc) revealed that microbiota-derived histamine (non-dietary origin) significantly exacerbated skin inflammation in a psoriasis model and induced γδT17 cell expansion across multiple immune organs. These effects were abolished in γδT cell-deficient mice. RNA sequencing demonstrated that histamine exposure upregulated the histamine receptor gene Hrh1 and activated the Wnt signaling pathway via pathway enrichment analysis. Further in vitro experiments confirmed that histamine promoted γδT17 cell differentiation in an Hrh1 receptor-dependent manner, with this process being associated with Wnt pathway activity. Our findings elucidate that gut microbiota-derived histamine exacerbates psoriatic inflammation by coordinately regulating the Hrh1 receptor and Wnt signaling pathway to drive γδT17 cell differentiation, providing a theoretical foundation for therapeutic strategies targeting microbial metabolites.
肠道微生物源性组胺通过Hrh1/Wnt轴促进γδT17细胞分化,从而加重银屑病
牛皮癣与肠道菌群失调和组胺水平异常升高有关,但微生物源性组胺的病理作用尚不清楚。在这项研究中,产生组胺的工程大肠杆菌(BL21_pET-17b_hdc)在小鼠体内的定殖表明,微生物来源的组胺(非饮食来源)显著加剧了牛皮癣模型的皮肤炎症,并诱导γδT17细胞在多个免疫器官上扩增。这些作用在γδT细胞缺陷小鼠中被消除。RNA测序结果表明,通过通路富集分析,组胺暴露可上调组胺受体基因Hrh1,激活Wnt信号通路。进一步的体外实验证实,组胺以Hrh1受体依赖的方式促进γδT17细胞分化,这一过程与Wnt通路活性有关。我们的研究结果阐明了肠道微生物源性组胺通过协调调节Hrh1受体和Wnt信号通路来驱动γδT17细胞分化,从而加剧银屑病炎症,为针对微生物代谢物的治疗策略提供了理论基础。
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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
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