Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models
Dechun Feng, … , George Kunos, Bin Gao
Dechun Feng, … , George Kunos, Bin Gao
Published June 20, 2023
Citation Information: J Clin Invest. 2023;133(15):e166954. https://doi.org/10.1172/JCI166954.
View: Text | PDF
Research Article Gastroenterology Hepatology

Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models

Abstract

The liver can fully regenerate after partial resection, and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury, with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here, we demonstrate that monocyte-derived macrophages (MoMFs) were rapidly recruited to and encapsulated necrotic areas during immune-mediated liver injury and that this feature was essential in repairing necrotic lesions. At the early stage of injury, infiltrating MoMFs activated the Jagged1/notch homolog protein 2 (JAG1/NOTCH2) axis to induce cell death–resistant SRY-box transcription factor 9+ (SOX9+) hepatocytes near the necrotic lesions, which acted as a barrier from further injury. Subsequently, necrotic environment (hypoxia and dead cells) induced a cluster of complement 1q–positive (C1q+) MoMFs that promoted necrotic removal and liver repair, while Pdgfb+ MoMFs activated hepatic stellate cells (HSCs) to express α–smooth muscle actin and induce a strong contraction signal (YAP, pMLC) to squeeze and finally eliminate the necrotic lesions. In conclusion, MoMFs play a key role in repairing the necrotic lesions, not only by removing necrotic tissues, but also by inducing cell death–resistant hepatocytes to form a perinecrotic capsule and by activating α-smooth muscle actin–expressing HSCs to facilitate necrotic lesion resolution.

Authors

Dechun Feng, Xiaogang Xiang, Yukun Guan, Adrien Guillot, Hongkun Lu, Chingwen Chang, Yong He, Hua Wang, Hongna Pan, Cynthia Ju, Sean P. Colgan, Frank Tacke, Xin Wei Wang, George Kunos, Bin Gao

×

Figure 7

Hypoxia triggers reprogramming of MoMFs in necrotic areas, contributing to the late stages of liver-injury resolution.

Options: View larger image (or click on image) Download as PowerPoint
Hypoxia triggers reprogramming of MoMFs in necrotic areas, contributing ...
(A and B) WT and C1q–/– mice were treated with ConA, followed by treatment with PBS or CA-074 Me 48 and 72 hours after ConA injection. Liver tissues were collected 96 hours after ConA injection. Representative H&E staining of liver tissue is shown (A, n = 4-7). Quantification of necrotic area is shown in B. (C) C57BL/6 mice were treated with ConA for 72 hours. Liver tissues were collected for IBA1/hypoxia probe staining and HIF1α/IBA1 double staining. Representative images are shown (n = 5). (D) WT and Hif1amye–/– mice were treated with ConA for 72 hours. Liver tissues were collected for double staining with various antibodies, as indicated (n = 5). Quantification of the percentage of positive cells is shown. (E) MoMFs from ConA-treated mice were isolated for bead uptake assay (n = 6–7). (F) WT and Hif1amye–/– mice were treated with ConA for 96 hours. Liver tissues were collected for H&E staining, and quantification of necrotic areas is shown on the right (n = 4). Dashed lines indicate the borders of necrotic areas. Values in B, D, E, and F are represented as means ± SD. Statistical significance was assessed using 2-tailed Student’s t test for comparing 2 groups (D–F) and 1-way ANOVA followed by Tukey’s post hoc test for multiple groups (B). **P < 0.01; ***P < 0.001.