期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2213041119
关键词
inflammatory bowel disease; bile acids; FXR; innate lymphoid cells; IL17
资金
- NIH [DK057978, HL105278, HL088093]
- National Cancer Institute [CA014195]
- National Health and Medical Research Council of Australia [1087297]
- Leona M. and Harry B. Helmsley Charitable Trust [2017PG-MED001]
- SWCRF Investigator Award
- Hewitt Medical Foundation Fellowship
- Salk Alumni Fellowship
- Crohn's & Colitis Foundation (CCFA) Visiting IBD Research Fellowship
- Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant [SU2C- AACR-DT-20-16]
- HHMI, March of Dimes Chair in Molecular and Developmental Biology
- NOMIS Foundation Distinguished Scientist and Scholar at the Salk Institute
- National Institute of Environmental Health Sciences of the National Institutes of Health [P42ES010337]
The activation of FXR selectively in the intestine has been shown to be protective in inflammation-driven models of IBD. FXR regulates innate lymphoid cells, blocking the increase of ILCs and the production of inflammatory cytokines. In addition, FXR is involved in the maturation/differentiation of ILC precursor cells.
The pleiotropic actions of the Farnesoid X Receptor (FXR) are required for gut health, and reciprocally, reduced intestinal FXR signaling is seen in inflammatory bowel diseases (IBDs). Here, we show that activation of FXR selectively in the intestine is protective in inflammation-driven models of IBD. Prophylactic activation of FXR restored homeostatic levels of pro-inflammatory cytokines, most notably IL17. Importantly, these changes were attributed to FXR regulation of innate lymphoid cells (ILCs), with both the inflammation-driven increases in ILCs, and ILC3s in particular, and the induction of Il17a and Il17f in ILC3s blocked by FXR activation. Moreover, a population of ILC precursor-like cells increased with treatment, implicating FXR in the maturation/ differentiation of ILC precursors. These findings identify FXR as an intrinsic regulator of intestinal ILCs and a potential therapeutic target in inflammatory intestinal diseases.
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