ADAM17 as a proteolytic rheostat linking inflammation, tissue repair, and failure of inflammatory resolution in liver injury and fibrosis.
TL;DR
This framework suggests that therapeutic strategies should move beyond broad ADAM17 inhibition toward context-, cell-, or substrate-selective modulation that limits pathogenic signaling while preserving inflammation-resolving and tissue-repair functions.
Abstract
A disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound sheddase that regulates inflammatory signaling, tissue repair, and fibrotic remodeling by converting cell-surface proteins into soluble forms. Rather than viewing ADAM17 simply as a proinflammatory enzyme, this review frames it as a proteolytic rheostat that dynamically adjusts the balance between membrane-bound and soluble molecular states in the injured liver. Within this framework, apparently opposing effects of ADAM17 can be understood as substrate-, cell-, and disease-stage-dependent consequences of ectodomain shedding. We particularly highlight two independently observed patterns of macrophage receptor-state remodeling: insufficient MerTK shedding may preserve profibrotic MerTK/ERK/TGF-β1 signaling, whereas excessive TREM2 shedding may reduce efferocytic capacity and contribute to failed inflammatory resolution. We further discuss how ADAM17-mediated shedding reshapes hepatocyte-macrophage-HSC communication and how soluble shedding products may provide circulating readouts of these processes. This framework suggests that therapeutic strategies should move beyond broad ADAM17 inhibition toward context-, cell-, or substrate-selective modulation that limits pathogenic signaling while preserving inflammation-resolving and tissue-repair functions.