Full Text | PDF

Theranostics 2024; 14(5):2210-2231. doi:10.7150/thno.87791 This issue Cite

Research Paper

Intravital imaging of splenic classical monocytes modifying the hepatic CX3CR1⁺ cells motility to exacerbate liver fibrosis via spleen-liver axis

Chenlu Han¹, Yujie Zhai¹, Yuke Wang¹, Xuwen Peng¹, Xian Zhang¹, Bolei Dai¹, Yuehong Leng¹, Zhihong Zhang^1,2✉, Shuhong Qi^1✉

1. Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
2. State key laboratory of digital medical engineering, School of Biomedical Engineering, Hainan University, Haikou, Hainan 570228, China.

✉ Corresponding authors: Zhihong Zhang, czyzzhhust.edu.cn; Shuhong Qi, qishuhongedu.cn. Address: Room G304, Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China. Fax: +86-27-87792034; Tel.: +86-27-87792033. More

Abstract

CX3CR1⁺ cells play a crucial role in liver fibrosis progression. However, changes in the migratory behavior and spatial distribution of spleen-derived and hepatic CX3CR1⁺ cells in the fibrotic liver as well as their influence on the liver fibrosis remain unclear.

Methods: The CX3CR1^GFP/+ transgenic mice and CX3CR1-KikGR transgenic mice were used to establish the CCl4-induced liver fibrosis model. Splenectomy, adoptive transfusion of splenocytes, in vivo photoconversion of splenic CX3CR1⁺ cells and intravital imaging were performed to study the spatial distribution, migration and movement behavior, and regulatory function of CX3CR1⁺ cells in liver fibrosis.

Results: Intravital imaging revealed that the CX3CR1^GFP cells accumulated into the fibrotic liver and tended to accumulate towards the central vein (CV) in the hepatic lobules. Two subtypes of hepatic CX3CR1⁺ cells existed in the fibrotic liver. The first subtype was the interacting CX3CR1^GFP cells, most of which were observed to distribute in the liver parenchyma and had a higher process velocity; the second subtype was mobile CX3CR1^GFP cells, most of which were present in the hepatic vessels with a faster moving speed. Splenectomy ameliorated liver fibrosis and decreased the number of CX3CR1⁺ cells in the fibrotic liver. Moreover, splenectomy rearranged CX3CR1^GFP cells to the boundary of the hepatic lobule, reduced the process velocity of interacting CX3CR1^GFP cells and decreased the number and mobility of mobile CX3CR1^GFP cells in the fibrotic liver. Transfusion of spleen-derived classical monocytes increased the process velocity and mobility of hepatic endogenous CX3CR1^GFP cells and facilitated liver fibrosis progression via the production of proinflammatory and profibrotic cytokines. The photoconverted splenic CX3CR1⁺ KikRed⁺ cells were observed to leave the spleen, accumulate into the fibrotic liver and contact with hepatic CX3CR1⁺ KikGreen⁺ cells during hepatic fibrosis.

Conclusion: The splenic CX3CR1⁺ monocytes with classical phenotype migrated from the spleen to the fibrotic liver, modifying the migratory behavior of hepatic endogenous CX3CR1^GFP cells and exacerbating liver fibrosis via the secretion of cytokines. This study reveals that splenic CX3CR1⁺ classical monocytes are a key driver of liver fibrosis via the spleen-liver axis and may be potential candidate targets for the treatment of chronic liver fibrosis.

Keywords: liver fibrosis, hepatic and splenic CX3CR1⁺ cells, spatial localization, movement behavior, spleen-liver axis

Citation styles

©2024 Ivyspring International Publisher. Terms of use