The Hepatic Crown-like Structure: A Focal Point for Macrophage Evolution and Disease Response in Steatotic Liver Disease

The hepatic crown-like structure (hCLS) is a shell-like aggregate of macrophages surrounding a large lipid-laden dying hepatocyte. This feature was initially assumed to simply be a response to increased inflammatory stress during steatotic liver disease, but recent studies have shown that the hCLS is a critical site for lipid processing, inflammation regulation, fibrosis modulation and macrophage development. Furthermore, advances in lineage tracing and transcriptomic analysis have provided information on the nature of the macrophage subtypes present in the hCLS. The hCLS consists of a heterogeneous mixture of macrophages that arise largely from bone marrow-derived infiltrating macrophages (IMs) but also have some of the properties of Kupffer cells (KCs). Most of the cells are variations of Lipid-Associated Macrophages (LAMs) expressing surface proteins such as GPNMB, TREM2, CD9, CD36, CD63 and CD11c. In addition, a class of LAM-like KCs is also present and these typically express many of the LAM proteins along with KC lineage proteins such as VSIG4 and CLEC4F. The hCLS plays an important role in lipid disposition and inflammation but conflicting evidence appears to support roles in fibrogenesis, extracellular matrix remodeling, and matrix degradation. This review aims to describe the critical findings and discoveries made regarding hCLSs and their role in macrophage development and function in steatotic liver diseases.