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Πέμπτη 2 Νοεμβρίου 2017

Deletion of neuropilin 1 from microglia or bone marrow-derived macrophages slows glioma progression

Glioma-associated microglia and macrophages (GAM) which infiltrate high-grade gilomas represent constitute a major cellular component of these lesions. GAM behavior is influenced by tumor-derived cytokines that suppress initial anti-tumorigenic properties, causing them to support tumor growth and to convert and suppress adaptive immune responses to the tumor. Mice which lack the transmembrane receptor neuropilin-1 (Nrp1) which modulates GAM immune polarization exhibit a decrease in glioma volumes and neoangiogenesis and an increase in anti-tumorigenic GAM infiltrate. Here we show that replacing the peripheral macrophage populations of wild type mice with Nrp1-depleted bone marrow-derived macrophages (BMDM) confers resistance to the development of glioma. This resistance occurred in a similar fashion seen in mice in which all macrophages lacked Nrp1 expression. Tumors had decreased volumes, decreased vascularity, increased CTL infiltrate, and Nrp1-depleted BMDM adopted a more anti-tumorigenic phenotype relative to wild type GAM within the tumors. Mice with Nrp1-deficient microglia and wild type peripheral macrophages showed resistance to glioma development and had higher microglial infiltrate than mice with wild type GAM. Our findings show how manipulating Nrp1 in either peripheral macrophages or microglia reprograms their phenotype and relieve their pathogenic roles in tumor neovascularization and immunosuppression.

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