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. 2025 Oct 2;188(20):5487-5498.e16.
doi: 10.1016/j.cell.2025.06.046. Epub 2025 Jul 24.

Mast cells regulate the brain-dura interface and CSF dynamics

Tornike Mamuladze  1 , Tiago H Zaninelli  2 , Leon C D Smyth  3 , Yue Wu  4 , Daviti Abramishvili  3 , Ruben Silva  3 , Brian Imbiakha  5 , Daan Verhaege  3 , Siling Du  6 , Zachary Papadopoulos  3 , Xingxing Gu  3 , David Lee  3 , Steffen Storck  3 , Richard J Perrin  7 , Igor Smirnov  3 , Xinzhong Dong  8 , Song Hu  4 , Michael S Diamond  9 , Felipe A Pinho-Ribeiro  2 , Jonathan Kipnis  10
Affiliations

Mast cells regulate the brain-dura interface and CSF dynamics

Tornike Mamuladze et al. Cell. .

Abstract

Cerebrospinal fluid (CSF) flow is essential for brain homeostasis, and its disruption is implicated in neurodegenerative and neuroinflammatory diseases. Arachnoid cuff exit (ACE) points, anatomical discontinuities in the arachnoid mater around bridging veins, serve as key sites of CSF-dura exchange. Here, we show that dural mast cells regulate CSF dynamics at ACE points. Upon degranulation, mast cells release histamine, inducing vasodilation of bridging veins and reducing perivascular spaces critical for CSF drainage. During bacterial meningitis, pathogens exploit ACE points to access the brain. However, mast cell activation redirects CSF flow, recruits neutrophils, and limits bacterial invasion. Mice lacking dural mast cells exhibit impaired immune responses and higher brain bacterial loads. These findings reveal dural mast cells as central players in modulating CSF flow and meningeal immunity. Targeting mast cells or their mediators may enhance CNS clearance and defense mechanisms, offering a potential therapeutic avenue for brain infections.

Keywords: ACE points; brain; bridging veins; cerebrospinal fluid; mast cells; meninges; meningitis.

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Conflict of interest statement

Declaration of interests J.K. is a co-founder of Rho Bio. M.S.D. is a consultant or advisor for Inbios, Moderna, IntegerBio, Merck, GlaxoSmithKline, Bavarian Nordic, and Akagera Medicines. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Emergent BioSolutions, Bavarian Nordic, Moderna, and IntegerBio.

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