Membrane IL-18 identifies a human macrophage subset with distinct proteomic and functional traits

Area of Science:

• Immunology
• Cell Biology
• Oncology

Background:

• Macrophages play critical roles in both normal physiological processes and pathological conditions, including cancer.
• Understanding macrophage heterogeneity is crucial for deciphering their impact on disease progression.

Purpose of the Study:

• To characterize a novel population of human macrophages expressing membrane-associated IL-18 (mIL-18).
• To investigate the proteomic, phenotypic, ultrastructural, and functional properties of mIL-18+ macrophages.
• To determine the role of mIL-18+ macrophages in cancer and other pathological conditions.

Main Methods:

• Proteomic analysis to identify key proteins.
• Phenotypic and ultrastructural characterization.
• Functional assays assessing cellular processes.
• Analysis of mIL-18+ macrophage presence in patient samples (peritoneal fluid, bone marrow).

Main Results:

• mIL-18+ macrophages possess unique proteomic profiles with increased proteins for pathogen recognition, activation, migration, and endocytosis.
• These cells show specialized functions in vesicle transport, actin dynamics, lipid metabolism, and distinct mitochondrial features.
• mIL-18+ macrophages are dominant in the peritoneal fluid of adult cancer patients and found in pediatric neuroblastoma bone marrow.
• TREM2 expression is high, while FOLR2 expression is heterogeneous, indicating distinct mIL-18+ macrophage subsets.
• Transcriptional signatures linked to mIL-18 expression have variable prognostic value in neuroblastoma.

Conclusions:

• mIL-18+ macrophages represent a distinct subset with unique functional capabilities.
• These macrophages are prevalent in the tumor microenvironment and exhibit significant heterogeneity.
• The heterogeneity of mIL-18+ macrophages may differentially impact tumor progression, highlighting their complex role in cancer.