Sphingosine-1-Phosphate Signalling Inhibition Suppresses Th1-Like Treg Generation by Reversing Mitochondrial Uncoupling.

IF 4.9 3区 医学 Q2 IMMUNOLOGY
Immunology Pub Date : 2025-01-01 Epub Date: 2024-10-24 DOI:10.1111/imm.13870
Rachel Coulombeau, Claudia Selck, Nicolas Giang, Abdulrahman Al-Mohammad, Natalie Ng, Allison K Maher, Rafael Argüello, Antonio Scalfari, James Varley, Richard Nicholas, Margarita Dominguez-Villar
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引用次数: 0

Abstract

Inflammatory environments induce the generation of dysfunctional IFNγ+T-bet+FOXP3+ Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1-like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1-like Tregs in vitro. Finally, these results are validated in in vivo-generated Th1-like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1-like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1-like Tregs.

鞘氨醇-1-磷酸信号抑制通过逆转线粒体解偶联抑制 Th1 类 Treg 的生成
炎症环境会诱导产生功能失调的 IFNγ+T-bet+FOXP3+ Th1 样 Tregs,这些 Tregs 显示出功能缺陷,并出现在包括多发性硬化症(MS)在内的自身免疫性疾病中。控制 Th1 样 Tregs 生成的途径尚不十分清楚。在 Th1 样 Tregs 中,Sphingosine-1-phosphate(S1P)信号分子上调,用 Fingolimod(FTY720)抑制体内 S1P 可抑制多发性硬化症患者中负责 Treg 可塑性的基因的表达。然而,其潜在机制尚不清楚。在这里,我们展示了通过 FTY720 抑制 S1P 信号可抑制 Th1 样 Tregs 的生成并挽救其抑制功能。这些效应是通过减少 mTORC1 信号传导和逆转线粒体解偶联介导的,Tregs 在体外重编程为 Th1 样 Tregs 的过程中经历了线粒体解偶联。最后,这些结果在体内生成的 Th1 样 Tregs 中得到了验证,因为接受 FTY720 治疗的多发性硬化症患者的 Tregs 显示 Th1 样 Treg 频率降低、抑制功能增强和线粒体代谢恢复平衡。这些结果突显了线粒体解偶联在 Treg 重编程中的参与作用,并确定 S1P 信号抑制是抑制 Th1-like Tregs 功能障碍生成的一个靶点。
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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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