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FXR 介导 ILC 固有反应对肠道炎症的作用。

FXR mediates ILC-intrinsic responses to intestinal inflammation.

机构信息

Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.

Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead NSW 2145, Australia.

出版信息

Proc Natl Acad Sci U S A. 2022 Dec 20;119(51):e2213041119. doi: 10.1073/pnas.2213041119. Epub 2022 Dec 12.

DOI:10.1073/pnas.2213041119
PMID:36508655
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9907109/
Abstract

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 and  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.

摘要

法尼醇 X 受体 (FXR) 的多效作用对于肠道健康是必需的，而反过来，在炎症性肠病 (IBD) 中则观察到肠道 FXR 信号转导减少。在这里，我们表明，FXR 在肠道中的选择性激活在 IBD 的炎症驱动模型中具有保护作用。FXR 的预防性激活恢复了促炎细胞因子的稳态水平，特别是 IL17。重要的是，这些变化归因于 FXR 对先天淋巴细胞 (ILCs) 的调节，包括 ILCs 的炎症驱动增加，特别是 ILC3s 的增加，以及 FXR 激活阻断了和  在 ILC3s 中的诱导。此外，随着治疗的进行，ILC 前体细胞样细胞的数量增加，这表明 FXR 参与了 ILC 前体细胞的成熟/分化。这些发现确定了 FXR 是肠道 ILC 的内在调节剂，也是炎症性肠道疾病的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/28e73cf623d4/pnas.2213041119fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/e786e497aeb8/pnas.2213041119fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/53f1c1cfd8f5/pnas.2213041119fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/7d822aa547e2/pnas.2213041119fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/28e73cf623d4/pnas.2213041119fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/e786e497aeb8/pnas.2213041119fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/53f1c1cfd8f5/pnas.2213041119fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/7d822aa547e2/pnas.2213041119fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fca5/9907109/28e73cf623d4/pnas.2213041119fig04.jpg

相似文献

[1]
FXR mediates ILC-intrinsic responses to intestinal inflammation.

Proc Natl Acad Sci U S A. 2022-12-20

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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引用本文的文献

[1]
Reversing metabolic dysregulation in farnesoid X receptor knockout mice via gut microbiota modulation.

PLoS One. 2025-9-5

[2]
Unraveling the Converging Roles of ASC-Dependent Inflammasomes, Interleukin-1 Superfamily Members, Serum Amyloid A, and Non-Sterile Inflammation in Disease Pathology and Fibrosis in Inflammatory Bowel Disease and Primary Sclerosing Cholangitis.

Int J Mol Sci. 2025-8-20

[3]
Faecalibacterium prausnitzii Ameliorates DSS-Induced Colitis via Modulating Bile Acid Metabolism and Regulating FXR Signaling.

Dig Dis Sci. 2025-7-5

[4]
Advances of exosome regulating‑FXR to repair inflammatory bowel disease (Review).

Int J Mol Med. 2025-9

[5]
Oleuropein Regulates Bile Acid Metabolism via Modulating the Gut Microbiota, Thereby Alleviating DSS-Induced Ulcerative Colitis in Mice.

Foods. 2025-5-23

[6]
Crosstalk Between Bile Acids and Intestinal Epithelium: Multidimensional Roles of Farnesoid X Receptor and Takeda G Protein Receptor 5.

Int J Mol Sci. 2025-4-29

[7]
Human umbilical cord mesenchymal stem cell-derived exosomes repair IBD by activating the SIRT1-FXR pathway in macrophages.

Stem Cell Res Ther. 2025-5-9

[8]
Review of the mechanisms of the biliary-enteric axis in the development of cholangiocarcinoma.

World J Clin Oncol. 2025-4-24

[9]
Phenotyping the Chemical Communications of the Intestinal Microbiota and the Host: Secondary Bile Acids as Postbiotics.

Cells. 2025-4-15

[10]
Pterostilbene attenuates intestinal barrier damage and secondary liver oxidative stress in a murine model of infection by regulating the gut microbiota.

Food Funct. 2025-5-6

本文引用的文献

[1]
Differential Modulation of Human Innate Lymphoid Cell (ILC) Subsets by IL-10 and TGF-β.

Sci Rep. 2019-10-4

[2]
Circadian rhythm-dependent and circadian rhythm-independent impacts of the molecular clock on type 3 innate lymphoid cells.

Sci Immunol. 2019-10-4

[3]
A circadian clock is essential for homeostasis of group 3 innate lymphoid cells in the gut.

Sci Immunol. 2019-10-4

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Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis.

Nature. 2019-9-18

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Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.

Cell. 2019-8-29

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Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet.

Cell. 2019-8-22

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Publisher Correction: Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues.

Nat Immunol. 2019-10

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Characterization of Transcriptional Regulatory Networks that Promote and Restrict Identities and Functions of Intestinal Innate Lymphoid Cells.

Immunity. 2019-7-2

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c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies.

Nat Immunol. 2019-7-1

[10]
Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease.

Immunity. 2019-4-16

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