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骨桥蛋白可用于鉴定胆管所关联的巨噬细胞，并与原发性硬化性胆管炎的肝纤维化严重程度相关。

Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis.

机构信息

Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium.

Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.

出版信息

Hepatology. 2024 Feb 1;79(2):269-288. doi: 10.1097/HEP.0000000000000557. Epub 2023 Aug 2.

DOI:10.1097/HEP.0000000000000557
PMID:37535809
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10789378/
Abstract

BACKGROUND AND AIMS

Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood.

APPROACH AND RESULTS

We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in-depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident KCs, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 ( Trem2 ) and osteopontin ( Spp1 ), markers assigned to hepatic bile duct-associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, and enhanced cholestasis-induced MoMF- Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro , while monoclonal antibody-mediated neutralization of SPP1 conferred protection in experimental PSC. In human PSC patients, serum osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as a prognostic biomarker for liver transplant-free survival.

CONCLUSIONS

Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as a prognostic marker and future therapeutic target in PSC.

摘要

背景与目的

原发性硬化性胆管炎（PSC）是一种免疫介导的胆汁淤积性肝病，目前尚无药物治疗选择。PSC 与结肠炎和肠道-肝脏轴的破坏密切相关，巨噬细胞参与 PSC 的发病机制。然而，肠道-肝脏相互作用和特定的巨噬细胞群体如何导致 PSC 尚不完全清楚。

方法和结果

我们研究了胆汁淤积和结肠炎对肝脏和结肠微环境的影响，并在同时伴有胆管炎和结肠炎的模型中对肝脏巨噬细胞动态和功能进行了深入表征。胆汁淤积诱导的纤维化表现为驻留 KC 的耗竭，以及单核细胞和单核细胞衍生的巨噬细胞（MoMF）在肝脏中的富集。这些 MoMF 高度表达触发受体表达在髓样细胞-2（Trem2）和骨桥蛋白（Spp1），这些标志物被分配给肝内胆管相关巨噬细胞，并在门三联体周围富集，这在人类 PSC 中得到了证实。结肠炎诱导单核细胞/巨噬细胞在肠道和肝脏中的浸润，并增强胆汁淤积诱导的 MoMF-Trem2 和 Spp1 上调，但不会加重肝纤维化。骨髓嵌合体表明，浸润的 MoMF 中 Spp1 的敲除会加剧体内和体外的炎症，而单克隆抗体介导的 SPP1 中和则在实验性 PSC 中提供保护。在人类 PSC 患者中，与对照组相比，血清骨桥蛋白水平升高，在晚期 PSC 中显著升高，可能作为无肝移植生存的预后生物标志物。

结论

我们的数据阐明了 PSC 中肠道-肝脏轴的紊乱和巨噬细胞的动态和功能，并强调了 SPP1/OPN 作为 PSC 的预后标志物和未来治疗靶点。

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