Spatially-resolved macrophage phenotyping in liver disease-related research

This review manuscript highlights the relevance of spatially-resolved macrophage phenotyping in liver disease-related research.

The liver is an important organ heavily populated with macrophages, which represent key players of the innate immune response but in addition hold key functions in the upkeep of a healthy organ. Liver macrophages are mostly distributed across two populations of various origins and functions during homeostasis and disease: liver resident macrophages (known as Kupffer cells, KCs), and monocytic macrophages derived from the bone-marrow (MoMFs). The KC: MoMF ratio, in addition to their respective spatial distribution through the liver, are increasingly recognized as liver disease progression hallmarks. These phenomena are observed in a wide range of liver diseases starting from non-alcoholic fatty liver disease to biliary tree disorders (cholangiopathies).

Recent single cell analyses revealed previously underestimated heterogeneities inside those two major populations. These studies were rendered possible by recent technological breakthroughs in transcriptomics, proteomics and bioinformatics, particularly in single cell RNA sequencing and multiplex immunostaining. Nowadays, the map of the liver macrophage landscape is being refined to incorporate this phenotypical and functional heterogeneity, in a 2- and three-d resolved manner.

Probably the most striking changes occurring at later stages of liver disease include a depletion in KCs and an accumulation of MoMFs with a powerful pro-inflammatory phenotype and poor phagocytosis capacities in perilobular fibrotic areas, while lipid-associated macrophages are observed in steatotic areas during fatty liver disease.