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

被引：5

作者：

Dong, Xingchen ^{[1
]}

Qi, Ming ^{[1
]}

Cai, Chunmiao ^{[1
]}

Zhu, Yu ^{[2
]}

Li, Yuwenbin ^{[3
]}

Coulter, Sally ^{[4
]}

Sun, Fei ^{[1
]}

Liddle, Christopher ^{[4
,5
]}

V. Uboha, Nataliya ^{[6
]}

Halberg, Richard ^{[7
]}

Xu, Wei ^{[7
]}

Marker, Paul ^{[1
]}

Fu, Ting ^{[1
,8
]}

机构：

[1] Univ Wisconsin, UWCCC, Sch Pharm, Pharmaceut Sci Div, Madison, WI 53705 USA

[2] Stanford Univ, Sch Med, Dept Pathol, Palo Alto, CA USA

[3] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA USA

[4] Univ Sydney, Westmead Hosp, Westmead Inst Med Res, Storr Liver Ctr, Westmead, NSW, Australia

[5] Univ Sydney, Westmead Hosp, Sydney Med Sch, Westmead, NSW, Australia

[6] UWCCC, Dept Med, Storr Liver Ctr, Westmead Inst Med Res, Madison, WI USA

[7] Univ Wisconsin, Sch Med & Publ Hlth, McArdle Lab Canc Res, Madison, WI 53705 USA

[8] Univ Wisconsin, Pharmaceut Sci Div, 777 Highland Ave, Madison, WI 53705 USA

来源：

JCI INSIGHT | 2024年 / 9卷 / 02期

关键词：

INTESTINAL CANCER; CYTOKINE NETWORKS; INNATE; ACID; INFLAMMATION; HOMEOSTASIS; MICROBIOTA; LIVER;

D O I：

10.1172/jci.insight.170428

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：23