Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair

Area of Science:

• Immunology
• Hepatology
• Cell Biology

Background:

• Limited understanding of functional differences between resident Kupffer cells (KCs) and recruited macrophages in liver disease.
• Lipid-associated macrophages (LAMs) are present in diseased livers, but their specific roles alongside KCs are unclear.

Purpose of the Study:

• To investigate the functional heterogeneity of macrophage subsets in the diseased liver.
• To elucidate the roles of recruited LAMs and resident KCs in liver injury and repair.

Main Methods:

• Proteogenomics to identify LAMs across various liver injury models.
• Genetic mouse models to target distinct macrophage populations.
• Analysis of TREM2 expression in resident and recruited macrophages.

Main Results:

• Identified LAMs in multiple liver injury models, with a LAM-like phenotype also observed in a subset of resident KCs (mouse and human).
• Both recruited LAMs and resident LAM-like KCs are essential for tissue repair.
• TREM2 expression on either macrophage type is critical for efficient efferocytosis (clearance of dying cells), promoting repair and mitigating fibrosis.

Conclusions:

• Macrophage heterogeneity in the liver includes both recruited LAMs and resident KCs adopting a LAM-like phenotype.
• TREM2-mediated efferocytosis by these macrophages is a key mechanism for liver repair and fibrosis prevention.