# Regulation of Neuroinflammation by Meningeal Lymphatics

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $210,750

## Abstract

PROJECT SUMMARY/ABSTRACT
The brain must maintain immunological homeostasis to prevent dysregulation and disease. Coordination of
immunity in most tissues involves the drainage of antigens or antigen-presenting cells within conventional
lymphatic vessels to the draining lymph nodes. In the lymph node, antigen presented to T cells, typically by
dendritic cells (DCs), can initiate an immune response. Control of immune response is unique in the central
nervous system as the brain parenchyma lacks conventional infiltrating lymphatic vessels and instead utilizes a
combination of intra-tissue glial-dependent clearance pathways and meningeal lymphatics surrounding the brain
to drain waste, antigens, fluid, and cells. Recently there has been mounting evidence implicating meningeal
lymphatic vessels as passive conductors of drainage in the progression, and resolution of various
neuropathologies. We previously discovered that neuroinflammation induces lymphangiogenesis of the
meningeal lymphatic vessels at the cribriform plate (cp) (Hsu et al. Nat Comm. 2019). We found that in situ
meningeal lymphangiogenesis was driven by VEGF-C producing DCs, and this is unique to the cp, highlighting
potentially different roles for dural lymphatics in neuroinflammation depending on their precise location. Here we
show single-cell RNA sequencing data revealing that neuroinflammation induces cribriform plate lymphatic
endothelial cell (cpLECs) gene expression related to antigen presentation, leukocyte adhesion, and
immunoregulation. This indicates that cpLECs are not just passive conductors of drainage, but active
contributors to the formation of a neuroimmune regulatory niche. We hypothesize that during neuroinflammation,
the cribriform lymphatics represent an immunoregulatory niche in which migratory DCs drained from the brain
are retained and communicate with cpLECs to regulate downstream immune response and homeostasis of the
central nervous system. The pathways of DCs traffic through the brain to the cribriform lymphatics, the
mechanism of their interaction with cpLECs, and the functional consequence of these interactions on both cell
types and on the formation of a neuroimmune niche are not known.
The long-term objective of this project is to define the pathways and dynamics of interactions between dendritic
cells and the cribriform plate lymphatics to understand the regulation of brain homeostasis and disease. The
specific objectives of this proposal are to map the timeline, origin, and mechanism of dendritic cell - cribriform
lymphatic endothelial cells interaction (DC-cpLEC) in the meningeal lymphatic vessels at the cribriform plate
(Aim 1); to define expressional consequences of the interaction between DCs and cpLECs (Aim 2), and to
examine the impact of DC-cpLEC interactions on lymphatic functionality and immunity (Aim 3).
Pharmacological manipulation of the cross-talk between dendritic cells and cribriform lymphatic endothelial cells
in CNS diseases may have po...

## Key facts

- **NIH application ID:** 10936943
- **Project number:** 3R01NS126595-02S1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Zsuzsanna Fabry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $210,750
- **Award type:** 3
- **Project period:** 2022-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936943

## Citation

> US National Institutes of Health, RePORTER application 10936943, Regulation of Neuroinflammation by Meningeal Lymphatics (3R01NS126595-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10936943. Licensed CC0.

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