National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy , The Second Affiliated Hospital, Xi'an Jiaotong University , Xi'an , China.
Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, CHESS-Shaanxi consortium , The Second Affiliated Hospital, Xi'an Jiaotong University , Xi'an , China.
Hepatology. 2023 May 1;77(5):1612-1629. doi: 10.1002/hep.32782. Epub 2023 Apr 17.
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.
单核细胞衍生的巨噬细胞（MoMFs）是炎症状态下肝脏巨噬细胞的主要群体，在肝纤维化进展中发挥关键作用。脾脏在炎症状态下是额外的单核细胞储存库；然而，脾脏参与肝纤维化发病机制的确切机制尚不清楚。
通过脾切除术和脾细胞输注，观察到脾 CD11b +细胞在体内积聚为 Ly6C lo MoMFs，从而加剧 CCl 4诱导的肝纤维化。通过 KikGR 小鼠对脾脏进行特异性光转化，并通过 CD45.1 + / CD45.2 +脾移植进一步直接观察到脾细胞向纤维性肝脏的迁移。然后，通过单细胞 RNA 测序对从纤维化肝脏中纯化的脾源性 CD11b +细胞进行注释，并鉴定出一种 CD11b + CD43 hi Ly6C lo 脾单核细胞（sM-1s）亚型，该亚型在纤维化肝脏的脾脏和肝脏中均显著扩增。sM-1s 表现出成熟特征，高水平表达 F4/80，产生大量 ROS，并表现出向肝脏的优先迁移。一旦被招募，sM-1s 就会经历连续的转化为 sM-2s（高表达 Mif 、Msr1 、Clec4d 和 Cstb ），然后转化为具有更高 CX 3 CR1 、F4/80 、MHC Ⅱ类和 CD64 表达的脾脏来源的巨噬细胞（sMφs）在纤维化的肝环境中。此外，sM-2s 和 sMφs 被证明能够激活肝星状细胞，从而加剧肝纤维化。
CD11b + CD43 hi Ly6C lo 脾单核细胞迁移到肝脏并转化为巨噬细胞，这导致了肝纤维化的加剧。这些发现揭示了脾脏-肝脏轴在肝脏发病机制中的精确机制，并为 sM-1 作为控制肝脏疾病的候选靶点提供了启示。
