Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis.
Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis.
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Farnesoid X受体拮抗巨噬细胞依赖性效应T淋巴细胞许可和硬化性胆管炎的进展。
DOI：
10.1126/scitranslmed.abi4354
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发表时间：
2022-12-14
影响因子：
17.1
通讯作者：
Miethke, Alexander G.
中科院分区：
文献类型：
--
作者：
Shi, Tiffany;Malik, Astha;vom Hofe, Annika Yang;Matuschek, Louis;Mullen, Mary;Lages, Celine S.;Kudira, Ramesh;Singh, Ruchi;Zhang, Wujuan;Setchell, Kenneth D. R.;Hildeman, David;Pasare, Chandrashekhar;Wagner, Brandee;Miethke, Alexander G.
免疫介导的胆管上皮损伤和保留的疏水胆汁酸的毒性驱动纤维化胆管病如胆道闭锁或原发性硬化性胆管炎的疾病进展。新兴疗法包括法尼醇X受体（FXR）的药理学激动剂，FXR是胆汁酸的肝脏合成、排泄和肠重摄取的主要调节剂。在阐明药理学FXR激动剂治疗硬化性胆管炎（SC）的作用机制后，我们发现，药物限制的FXR激活有效地减少了胆汁酸池的大小，但没有改善MDR 2 −/−小鼠的SC表型。相反，全身性FXR激活不仅降低胆汁酸合成，而且抑制肝脏浸润性炎症细胞产生促炎细胞因子，并阻断肝胆损伤的进展。其保肝作用与抑制肝巨噬细胞产生IL 1 β和TNFα及抑制TH 1/TH 17淋巴细胞极化有关。骨髓细胞中FXR的缺失导致二乙氧羰基-1，4-二氢可力丁诱导的SC中异常的TH 1和TH 17淋巴细胞应答，并使这些小鼠对全身FXR激动剂治疗的抗炎和肝脏保护作用产生抗性。药理学FXR激活可减少纤维化胆管病患者肝和血液来源的单核细胞产生IL 1 β和IFNγ。总之，我们证明FXR控制巨噬细胞-TH 1/17轴，这是至关重要的SC的进展。肝巨噬细胞是胆汁淤积性肝病的全身FXR激动剂治疗的细胞靶点。
Immune-mediated bile duct epithelial injury and toxicity of retained hydrophobic bile acids drive disease progression in fibrosing cholangiopathies such as biliary atresia or primary sclerosing cholangitis. Emerging therapies include pharmacological agonists to farnesoid X receptor (FXR), the master regulator of hepatic synthesis, excretion, and intestinal reuptake of bile acids. Unraveling the mechanisms of action of pharmacological FXR agonists in the treatment of sclerosing cholangitis (SC), we found that intestinally restricted FXR activation effectively reduced bile acid pool size but did not improve the SC phenotype in MDR2−/− mice. In contrast, systemic FXR activation not only lowered bile acid synthesis but also suppressed proinflammatory cytokine production by liver-infiltrating inflammatory cells and blocked progression of hepatobiliary injury. The hepatoprotective activity was linked to suppressed production of IL1β and TNFα by hepatic macrophages and inhibition of TH1/TH17 lymphocyte polarization. Deletion of FXR in myeloid cells caused aberrant TH1 and TH17 lymphocyte responses in diethoxycarbonyl-1,4-dihydrocollidine–induced SC and rendered these mice resistant to the anti-inflammatory and liver protective effects of systemic FXR agonist treatment. Pharmacological FXR activation reduced IL1β and IFNγ production by liver- and blood-derived mononuclear cells from patients with fibrosing cholangiopathies. In conclusion, we demonstrate FXR to control the macrophage-TH1/17 axis, which is critically important for the progression of SC. Hepatic macrophages are cellular targets of systemic FXR agonist therapy for cholestatic liver disease.
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影响因子：
3.7
作者：
Best J;Verhulst S;Syn WK;Lagaisse K;van Hul N;Heindryckx F;Sowa JP;Peeters L;Van Vlierberghe H;Leclercq IA;Canbay A;Dollé L;van Grunsven LA
通讯作者：
van Grunsven LA
影响因子：
16.6
作者：
Jain A;Song R;Wakeland EK;Pasare C
通讯作者：
Pasare C
DOI：
10.1002/hep.29676
发表时间：
2018-06
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hartmann P;Hochrath K;Horvath A;Chen P;Seebauer CT;Llorente C;Wang L;Alnouti Y;Fouts DE;Stärkel P;Loomba R;Coulter S;Liddle C;Yu RT;Ling L;Rossi SJ;DePaoli AM;Downes M;Evans RM;Brenner DA;Schnabl B
通讯作者：
Schnabl B
影响因子：
5.5
作者：
Boxio, R;Bossenmeyer-Pourié, C;Nüsse, O
通讯作者：
Nüsse, O
影响因子：
6
作者：
Fickert, Peter;Stoeger, Ulrike;Trauner, Michael
通讯作者：
Trauner, Michael