During liver regeneration active TGFb drives polarization of distinct CCR2-dependently recruited macrophage populations

Background & aims In the context of liver regeneration macrophages play an important regulatory role. Thereby the changes of the composition of the different macrophage populations and of their polarization during liver regeneration has not been investigated in detail. Likewise, the factors that mainly control this process as well as their relevance for undisturbed regeneration are unclear.

Methods Wild type animals, CCR2-/- mice and mice with myeloid cell specific deletion of the TGFβRII were analysed after partial hepatectomy (PHx). In addition, the impact of hepatocytes on macrophage polarization was studied using a coculture with highly purified hepatocytes which are embedded into a collagen matrix.

Results After PHx there is an CCR2-dependent increase in macrophages characterized by high expression of CD11b (F4/80+/CD11bhigh), while the number of low CD11b expressing macrophages (F4/80+/CD11blow) decreases significantly and only gradually increases again during the regeneration process. Thereby, CD11bhigh macrophages can be clearly further distinguished into two subgroups based on their CD14 expression and those characterized by high expression of CD11b and of CD14 show a temporary but early, rapid and strong increase during regeneration after PHx. Notably, these macrophages exhibit a particular polarization under homoeostatic conditions and, compared to the other macrophage populations of the liver, also undergo significant changes of their polarization in the course of the regeneration process. Moreover, their presence in the liver as well as their recruitment is CCR2 dependent, which is not the case for F4/80+/CD11blow/CD14low macrophages and only in part for those which are F4/80+/CD11bhigh/CD14low. The experiments further suggest that the availability of active TGFβ plays a role in the intercellular communication network by which hepatocytes influence the polarization of in particular F4/80+/CD11bhigh/CD14high macrophages and lack of the TGFβ receptor II in macrophages results in prolongation of the proliferation phase of hepatocytes, accelerated regeneration as well as reduced injury after PHx.

Conclusion Recruitment of macrophages into the regenerating liver is CCR2-dependent. Different macrophage populations are recruited into the regenerating liver, which differ substantially in their willingness to adapt their polarization. In this context, the availability of active TGFβ seems to play a role and influence the regeneration process.

Publication History

Article published online:
04 January 2021