肝细胞对肝巨噬细胞进行重编程，涉及 TGF-β 激活的控制，影响肝脏再生和损伤。

Hepatocytes reprogram liver macrophages involving control of TGF-β activation, influencing liver regeneration and injury.

机构信息

Department of Gastroenterology, Hepatology and Infectious Disease, Faculty of Medicine & Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany.

Institute for Computational Biomedicine, Faculty of Medicine & Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany.

出版信息

Hepatol Commun. 2023 Jul 24;7(8). doi: 10.1097/HC9.0000000000000208. eCollection 2023 Aug 1.

DOI:10.1097/HC9.0000000000000208

PMID:37486964

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10368377/

Abstract

BACKGROUND

Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in terms of their activation state and which other liver cell populations may play a role in regulating the same.

METHODS

Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy.

RESULTS

We show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)-dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow-derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell-specific deletion of the TGF-β type II receptor, suggest that the availability of activated TGF-β and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-βRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration.

CONCLUSIONS

The availability of activated TGF-β determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-β may represent an important regulatory mechanism in the early phase of liver regeneration in this context.

摘要

背景

巨噬细胞在维持肝脏内稳态和再生方面发挥着重要作用。然而，不同肝巨噬细胞群体在激活状态方面存在何种差异，以及其他何种肝细胞群体可能在调节这些差异方面发挥作用，目前尚不清楚。

方法

采用逆转录 PCR、流式细胞术、转录组学、蛋白质组学、分泌组学、单细胞分析和免疫组织化学方法，研究了在体内和体外的稳态条件下以及部分肝切除后，基因表达的变化以及巨噬细胞的激活状态。

结果

我们表明，肝脏中 F4/80+/CD11bhi/CD14hi 巨噬细胞是通过 C-C 基序趋化因子受体（CCR2）依赖性方式募集的，其激活状态与其他肝巨噬细胞群体明显不同，后者可基于 CD11b 和 CD14 的表达来区分。由此，原代肝细胞能够在体外创造一种环境，在骨髓来源的巨噬细胞中引发与体内 F4/80+/CD11bhi/CD14hi 肝巨噬细胞中观察到的相同特定激活状态。随后的分析，包括在骨髓细胞中特异性缺失 TGF-β 型 II 受体的小鼠研究表明，激活的 TGF-β 的可用性及其被肝细胞条件培养基下调是至关重要的。TGF-βRII 介导的信号转导在髓样细胞中的减少导致 IL-6、IL-10 和 SIGLEC1 表达的上调，这是 F4/80+/CD11bhi/CD14hi 巨噬细胞激活状态的标志，并增强了肝脏再生。