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

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 d...

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Main Authors: Luu, Maik, Krause, Felix K., Monning, Heike, Wempe, Anne, Leister, Hanna, Mainieri, Lisa, Staudt, Sarah, Ziegler-Martin, Kai, Mangold, Kira, Kappelhoff, Nora, Shaul, Yoav D., Göttig, Stephan, Plaza-Sirvent, Carlos, Schulte, Leon N., Bekeredjian-Ding, Isabelle, Schmitz, Ingo, Steinhoff, Ulrich, Visekruna, Alexander
Format: Article
Language:English
Published: Philipps-Universität Marburg 2024
Subjects:
Microbial metabolites
NF-kB
Microbiota
Regulatory B cells
Colitis
Medizin
Medical sciences Medicine
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Summary: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.
Item Description:Gefördert durch den Open-Access-Publikationsfonds der UB Marburg.
DOI:10.1016/j.mucimm.2024.09.003

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