Bile acid metabolites control Th17 and Treg cell differentiation
| Autor: | Soyoung Ha, Dan R. Littman, Brandon N. Nelson, Jingping Lu, Saiyu Hang, Michael A. Fischbach, Jamma Trinath, Michael R. Krout, Donggi Paik, Ye Zheng, Samantha P. Kelly, Lin Wu, Fraydoon Rastinejad, A. Sloan Devlin, Jun R. Huh |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Orphan receptor
Innate immune system Lithocholic acid Bile acid medicine.drug_class Cellular differentiation Immunology FOXP3 hemic and immune systems chemical and pharmacologic phenomena Cell biology chemistry.chemical_compound Immune system chemistry RAR-related orphan receptor gamma medicine Immunology and Allergy |
| Zdroj: | The Journal of Immunology. 204:230.6-230.6 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Bile acids are abundantly present in the mammalian gut, where they undergo bacteria-mediated transformation, generating a large pool of bioactive molecules. While they have been shown to affect host metabolism, cancer progression and innate immunity, it is unknown whether bile acids affect the function of adaptive immune cells such as T cells expressing IL-17a (Th17 cells) and regulatory T cells (Tregs) that mediate inflammatory and anti-inflammatory responses, respectively. By screening a small-molecule library primarily composed of bile acid metabolites, we identified two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as specific regulators of Th17 and Treg cells. While 3-oxoLCA inhibited Th17 cell differentiation by directly binding to its key transcription factor RORγt (retinoid-related orphan receptor γt), isoalloLCA enhanced Treg differentiation through the production of mitochondrial reactive oxygen species (mitoROS), leading to increased FoxP3 expression. IsoalloLCA-mediated Treg enhancement required an intronic FoxP3 enhancer the conserved noncoding sequence 3 (CNS3), suggesting a distinct mode of action from other previously identified Treg enhancing metabolites that require CNS1. Lastly, oral administration of 3-oxoLCA and isoalloLCA to mice led to reduced Th17 and increased Treg cell differentiation in the intestinal lamina propria. Altogether, our data suggest novel mechanisms by which bile acid metabolites control host immune responses by directly modulating the Th17 and Treg balance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|