Bile acid receptor Tgr5 prevents macrophage hyperinflammation during bacterial sepsis through metabolic and epigenetic silencing
Tgr5 is a membrane-bound bile acid receptor that negatively regulates immune cells, although the molecular mechanisms behind this observation remain elusive. Here we report that Tgr5 is upregulated in macrophages during stimulation with <i>Listeria monocytogenes</i> and that Tgr5-deficient macrophages are hyperinflammatory and mice with myeloid Tgr5 deficiency are more susceptible to <i>Listeria monocytogenes</i> sepsis. Unexpectedly, Tgr5-deficient macrophages show reduced glycolysis and ATP citrate lyase expression, which cumulates in acetyl-CoA deficiency and impaired metabolic-epigenetic gene silencing, driving macrophages toward a hyperinflammatory phenotype during bacterial sepsis.
Authors
- Philipp A. Lang (ORCID: https://orcid.org/0000-0001-5341-0407)
- Anja Sammt
- Paulina Philippski
- Maria Reich (ORCID: https://orcid.org/0009-0001-2052-8270)
- Jan Stindt (ORCID: https://orcid.org/0000-0002-8760-1989)
- Kristina Schoonjans (ORCID: https://orcid.org/0000-0003-1247-4265)
- Sascha Kahlfuß (ORCID: https://orcid.org/0000-0001-8813-1061)
- Haifeng Xu (ORCID: https://orcid.org/0000-0002-7999-0814)
- Tobias Franz (ORCID: https://orcid.org/0000-0003-2752-814X)
- Verena Keitel (ORCID: https://orcid.org/0000-0003-1383-7662)
- Sandra Freier
Institutions
- University Hospital Magdeburg (DE)
- Heinrich Heine University Düsseldorf (DE)
- École Polytechnique Fédérale de Lausanne (CH)
- Otto-von-Guericke-Universität Magdeburg (DE)
Publication Details
- Journal
- iScience
- Published
- 2025-11-06
- DOI
- https://doi.org/10.1016/j.isci.2025.113929
- Citations
- 1
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.05