Dissecting the metabolic signaling pathways by which microbial molecules drive the differentiation of regulatory B cells.

IF 7.9 2区 医学 Q1 IMMUNOLOGY Mucosal Immunology Pub Date : 2024-09-16 DOI:10.1016/j.mucimm.2024.09.003
Maik Luu,Felix F Krause,Heide Monning,Anne Wempe,Hanna Leister,Lisa Mainieri,Sarah Staudt,Kai Ziegler-Martin,Kira Mangold,Nora Kappelhoff,Yoav D Shaul,Stephan Göttig,Carlos Plaza-Sirvent,Leon N Schulte,Isabelle Bekeredjian-Ding,Ingo Schmitz,Ulrich Steinhoff,Alexander Visekruna
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Abstract

The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκBNS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal Clostridium sporogenes, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.
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剖析微生物分子驱动调节性 B 细胞分化的代谢信号通路。
宿主-微生物组轴与促进抗炎免疫反应有关。然而,共生菌介导调节性 B 细胞(Bregs)产生 IL-10 的潜在分子机制尚未完全阐明。在这里,我们证明了细菌的 CpG 基序触发了 TLR9 下游的信号传导,促进了 IκBNS 介导的 Blimp-1 (IL-10 的转录调节因子)的表达。令人惊讶的是,这种效应被 NF-κB 转录因子 c-Rel 所抵消。通过对肠道细菌种类进行功能筛选,发现共生梭状芽孢杆菌能分泌大量短链脂肪酸(SCFAs)和支链脂肪酸(BCFAs),通过促进 B 细胞中持续的 mTOR 信号传导来促进 IL-10 的产生。因此,通过将 CpG 与 SCFA 丁酸酯或 BCFA 异戊酸酯结合,从而协同 TLR 和 mTOR 介导的途径,可增强 Breg 的功能。总之,Bregs 需要两种细菌信号(丁酸盐和 CpG)才能激发其全部抑制能力并改善 T 细胞介导的肠道炎症。我们的研究剖析了细菌因子诱导的分子通路,这不仅有助于更好地理解宿主与微生物组的相互作用,还有助于探索改善抗炎细胞疗法的新策略。
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来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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