CD11b + CD43 hi Ly6C lo splenocyte-derived macrophages exacerbate liver fibrosis via spleen-liver axis

• Published in: Hepatology (Baltimore, Md.) Vol. 77; no. 5; pp. 1612 - 1629
• Main Authors: Zhang, Shaoying, Wan, Dan, Zhu, Mengchen, Wang, Guihu, Zhang, Xurui, Huang, Na, Zhang, Jian, Zhang, Chongyu, Shang, Qi, Zhang, Chen, Liu, Xi, Liang, Fanfan, Zhang, Chunyan, Kong, Guangyao, Geng, Jing, Yao, Libo, Lu, Shemin, Chen, Yongyan, Li, Zongfang
• Format: Journal Article
• Language: English
• Published: United States 01.05.2023
• Subjects: Animals; Liver - pathology; Liver Cirrhosis - pathology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Monocytes - metabolism; Spleen - pathology
• ISSN: 1527-3350
• DOI: 10.1002/hep.32782

Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of the spleen in the pathogenesis of liver fibrosis remain unclear. By splenectomy and splenocyte transfusion, it was observed that splenic CD11b + cells accumulated intrahepatically as Ly6C lo MoMFs to exacerbate CCl 4 -induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen-specific photoconversion with KikGR mice and confirmed by CD45.1 + /CD45.2 + spleen transplantation. Spleen-derived CD11b + cells purified from fibrotic livers were then annotated by single-cell RNA sequencing, and a subtype of CD11b + CD43 hi Ly6C lo splenic monocytes (sM-1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM-1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM-1s underwent sequential transformation to sM-2s (highly expressed Mif , Msr1 , Clec4d , and Cstb ) and then to spleen-derived macrophages (sMφs) with macrophage features of higher expressions of CX 3 CR1, F4/80, MHC class II, and CD64 in the fibrotic hepatic milieu. Furthermore, sM-2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis. CD11b + CD43 hi Ly6C lo splenic monocytes migrate into the liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen-liver axis in hepatic pathogenesis and shed light on the potential of sM-1 as candidate target for controlling liver diseases.