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

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

Summary: 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 generat...

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Main Authors: Yusra Zaidi, Rebekah Tritz, Nida Zaidi, Faisal Nabi, Syed Adeel H. Zaidi, Abdelhakim Morsy, Valerie Harris, Rilee Racine, Farlyn Z. Hudson, Zsuzsanna Bordan, Simone Kennard, Robert Batori, Yuqing Huo, Gabor Csanyi, Eric J. Belin de Chantemèle, Kecheng Lei, Nicholas M. Boulis, David J. Fulton, Rizwan Hasan Khan, Ruth B. Caldwell, Brian K. Stansfield
Format: Article
Language:English
Published: Elsevier 2025-05-01
Series:Cell Reports
Subjects:
CP: Immunology
CP: Metabolism
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725003961
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Summary:Summary: 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 (MIL4) macrophages to undergo an inflammatory phenotypic switch. Inflammatory MLPSIFNγ macrophages and inflammatory-like MIL4 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.
ISSN:2211-1247

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