Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.

Authors

Simone Brioschi, Julia A Belk, Steffen E Storck, Yue Wu, Zhuoying Wang, Ziang Feng, Lynn van Olst, Josie L Emery, Raki Sudan, Junjie Wu, Siling Du, Marco Genua, Federica La Terza, Alex J Edwards, Khai M Nguyen, Jessie Sanford, Daniel D Lee, Mattia Bugatti, Arnold J Federico, Yun Chen, Zuoxu Wang, Silvia Penati, Patrick Fernandes Rodrigues, Alina Ulezko Antonova, Hui Qi Loo, Igor Smirnov, Susan Gilfillan, Carmen M Halabi, Jennifer Ponce, Jun Yan, Howard Y Chang, Gwendalyn J Randolph, William Vermi, Marina Cella, Michael Meers, Renato Ostuni, David Gate, Aivi T Nguyen, Carlos Cruchaga, Song Hu, Jonathan Kipnis, Marco Colonna

Published in

Cell. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.

PMID:
42600613
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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