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<sup>IL4</sup>) macrophages to undergo an inflammatory phenotypic switch. Inflammatory M<sup>LPSIFNγ</sup> macrophages and inflammatory-like M<sup>IL4</sup> 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.
Authors
- Brian K. Stansfield (ORCID: https://orcid.org/0000-0002-1105-8895)
- Syed Zaidi (ORCID: https://orcid.org/0000-0002-9177-0881)
- Valerie Harris (ORCID: https://orcid.org/0000-0002-8577-4157)
- Simone Kennard (ORCID: https://orcid.org/0000-0002-7564-9192)
- Ruth B. Caldwell (ORCID: https://orcid.org/0000-0003-0168-0354)
- Farlyn Z. Hudson
- Rizwan Hasan Khan (ORCID: https://orcid.org/0000-0002-9965-8982)
- Kecheng Lei (ORCID: https://orcid.org/0000-0002-2607-8960)
- Yuqing Huo (ORCID: https://orcid.org/0000-0002-0305-4122)
- Yusra Zaidi (ORCID: https://orcid.org/0000-0002-1917-0398)
- Róbert Bátori (ORCID: https://orcid.org/0000-0002-1400-6732)
- Rebekah Tritz
- Eric J. Belin de Chantemèle (ORCID: https://orcid.org/0000-0002-0184-3830)
- Nida Zaidi (ORCID: https://orcid.org/0000-0003-2579-2190)
- Zsuzsanna Bordán (ORCID: https://orcid.org/0000-0002-8409-3712)
- Nicholas M. Boulis (ORCID: https://orcid.org/0000-0002-7271-3953)
- Gábor Csányi (ORCID: https://orcid.org/0000-0002-4429-3031)
- David Fulton (ORCID: https://orcid.org/0000-0002-1528-1517)
- Faisal Nabi (ORCID: https://orcid.org/0000-0002-5236-9905)
- Abdelhakim Morsy
- Rilee Racine
Institutions
- Georgia Institute of Technology (US)
- Emory University (US)
- Aligarh Muslim University (IN)
- Augusta University (US)
- Augusta University Health (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1016/j.celrep.2025.115625
- Citations
- 1
- Primary Topic
- Neurofibromatosis and Schwannoma Cases
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- Children's Tumor Foundation
- National Institutes of Health
- National Eye Institute