Loss of neurofibromin induces inflammatory macrophage phenotypic switch and retinal neovascularization via GLUT1 activation.

Persons with neurofibromatosis type 1 (NF1) exhibit enhanced glucose metabolism, which is replicated in Nf1-mutant mice. Inflammatory macrophages invest NF1-associated tumors, and targeting macrophages appears efficacious in NF1 models. Inflammatory macrophages rely on glycolysis to generate ATP; thus, identifying whether neurofibromin, the protein encoded by NF1, controls glucose metabolism in macrophages is therapeutically compelling. Using neurofibromin-deficient macrophages and macrophage-specific Nf1-knockout mice, we demonstrate that neurofibromin complexes with glucose transporter-1 (GLUT1) to restrain its activity and that loss of neurofibromin permits Akt2 to facilitate GLUT1 translocation to the membrane. In turn, glucose internalization and glycolysis are upregulated and provoke reparative (M^IL4) macrophages to undergo an inflammatory phenotypic switch. Inflammatory M^LPSIFNγ macrophages and inflammatory-like M^IL4 macrophages invest the perivascular stroma of tumors and induce pathologic angiogenesis in macrophage-specific Nf1-knockout mice. These studies identify a mechanism for the enhanced glycolysis associated with NF1 and provide a novel therapeutic target for NF1.