Membrane IL-18 Identifies a Unique Human Macrophage Subset with Distinct Phenotypic and Functional Properties

This study adds a tile to the macrophage heterogeneity in humans. We characterize a unique macrophage population expressing membrane-associated IL-18 (mIL-18) that shows peculiar proteomic, phenotypic, ultrastructural, and functional properties. mIL-18+ macrophages exhibit increased levels of key proteins for pathogen recognition, activation, migration, and endocytosis. They also display specialized functions in vesicle and actin filament transport, lipid metabolism, and have typical mitochondrial traits. mIL-18 identifies most macrophages in the peritoneum of adult cancer patients, where it is co-expressed with TREM2. Conversely, two populations of TREM2+ cells, either expressing or lacking mIL-18, colonize the bone marrow of pediatric patients with neuroblastoma, Importantly, in primary neuroblastomas, transcriptional signatures associated with mIL-18 expression show different prognostic values. These data indicate a potentiated role for the mIL-18+ macrophages in the surveillance of tumor- and inflammatory-associated microenvironments.