Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression
Xingchen Dong, Ming Qi, Chunmiao Cai, Yu Zhu, Yuwenbin Li, Sally Coulter, Fei Sun, Christopher Liddle, Nataliya V. Uboha, Richard Halberg, Wei Xu, Paul Marker, Ting Fu
Xingchen Dong, Ming Qi, Chunmiao Cai, Yu Zhu, Yuwenbin Li, Sally Coulter, Fei Sun, Christopher Liddle, Nataliya V. Uboha, Richard Halberg, Wei Xu, Paul Marker, Ting Fu
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Research Article Endocrinology Gastroenterology

Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression

Abstract

Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs’ profile in a mouse CAC model. Further, gut macrophage–intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines’ secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages’ recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

Authors

Xingchen Dong, Ming Qi, Chunmiao Cai, Yu Zhu, Yuwenbin Li, Sally Coulter, Fei Sun, Christopher Liddle, Nataliya V. Uboha, Richard Halberg, Wei Xu, Paul Marker, Ting Fu

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Figure 5

FXR regulates BMDMs’ polarization and functional maturation.

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FXR regulates BMDMs’ polarization and functional maturation. (A) Experim...
(A) Experimental scheme of BMDM polarization and crosstalk to T cells. Polarization details are described in Methods. After polarization, BMDMs were treated with FXR agonists, FexD and OCA, or vehicle for 6 hours (step 1). Naive T cells were isolated from the spleen of WT mice and subjected to IL6 and TGF-β for initial Th17 cell in vitro differentiation for 24 hours. Then, the supernatant of BMDMs was added to Th17 cells for another 48 hours (step 2). Cell samples and cultured supernatant were harvested for qRT-PCR and ELISA. (B and C) Expression of M1 (B) and M2 (C) marker genes measured by qRT-PCR in polarized M1 or M2 BMDMs with above treatment. (D) Secreted (IL6, TNF-α) and intracellular (IL1β) cytokines were measured by ELISA in M1 BMDMs with above treatment. (E) Expression of cytokine genes measured by qRT-PCR in Th17 cells in vitro differentiated with M1 BMDM supernatant. (F) The level of cytokines secreted by Th17 cells was measured by ELISA. (G and H) Expression of M1 (G) and M2 (H) marker genes measured by qRT-PCR in polarized M1 or M2 FXR-deficient BMDMs. n = 3/group. Experiments were independently replicated 3 times, and representative data are shown as the mean ± SEM. P values are computed with 1-way ANOVA test followed by Tukey’s multiple comparisons. *M1/M2 versus M0 in WT or FXR-KO groups, #FexD and OCA versus DMSO in WT or FXR-KO groups; *, #P < 0.05; **, ##P < 0.01; ***, ###P < 0.005.