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