# Role of the neurovascular molecule Wnt in regulating CNS inflammatory responses

> **NIH NIH R35** · UNIVERSITY OF CINCINNATI · 2022 · $356,907

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of our lab is to investigate immune regulation by innate cells for the treatment and resolution/repair of
central nervous system (CNS) inflammatory diseases. During neuroinflammation the concerted actions of the
CNS and the immune system affect the pathological responses mediated by infiltrating and resident immune
cells. In particular, during multiple sclerosis (MS), myeloid cells are found in abundance within lesions. These
myeloid antigen-presenting cells (APCs) have the ability to phagocytose myelin debris, release neurotoxic factors
and promote the expansion and polarization of T cells in the CNS. However, they can also antagonize
inflammation and promote repair. The exact mechanism(s) by which the CNS environment regulates myeloid
APCs function during neuroinflammation remains ill defined.
Analysis of the transcripts associated with MS-like lesions in experimental autoimmune encephalomyelitis (EAE),
an animal model of MS, revealed a significant enrichment of genes associated with the Wnt/b-catenin pathway
as compared to non-lesioned areas. Binding of Wnt proteins to the cell surface receptor Frizzled (Fzd) inhibits
glycogen synthase kinase 3b (GSK3b) and b-catenin phosphorylation, allowing b-catenin translocation to the
nucleus and activates transcription of Wnt target genes. It has been demonstrated that Wnt signaling in dendritic
cells (DCs) plays a central role in regulating the balance between inflammatory vs. regulatory responses in the
gut. Blockade of GSK3b kinase was shown to increase IL-10 production by monocytes while suppressing the
release of pro-inflammatory cytokines. In addition, our preliminary results demonstrate that following activation
of the Wnt/b-catenin pathway, PD-L1 and PD-L2 expression were increased on human and mouse myeloid cells,
while IL-1b, IL-6, IL-12 and IL-23 were reduced. Significantly, in EAE, Wnt agonist treatment decreased the
clinical severity of chronic and relapsing-remitting EAE.
Wnt proteins are naturally expressed in the CNS by brain endothelial cells (BBB-ECs) and astrocytes, and are
upregulated during neuroinflammation. These cells make the neurovascular unit (NVU), a structure serving as
an interface between the periphery and the CNS and hence directly exposed to the effects of peripheral and
CNS driven inflammation. We hypothesize that inflammatory signals at the neurovascular level induce Wnt
production by ECs and astroglial cells, which will regulate myeloid APCs function and promote anti-
inflammatory responses that support repair and limit neuropathology. Using in vitro and in vivo
approaches, our goal is to understand how Wnt ligands affect the immune response in the CNS and to determine
the possibility to manipulate it in order to regulate myeloid cell function to reduce CNS-inflammatory responses
and stimulate the repair mechanism.

## Key facts

- **NIH application ID:** 10499281
- **Project number:** 1R35GM146890-01
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Igal Ifergan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $356,907
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499281

## Citation

> US National Institutes of Health, RePORTER application 10499281, Role of the neurovascular molecule Wnt in regulating CNS inflammatory responses (1R35GM146890-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10499281. Licensed CC0.

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