# The integration of IL-17 and NOTCH signaling in the pathogenesis of CNS inflammation

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $351,458

## Abstract

Project Summary
Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS).
Increasing evidence indicates that the inhibition of remyelination is a major cause of the permanent
neurodegeneration. However the precise mechanism that inhibits OPCs differentiation and remyelination
remains an active area of research. While inflammation-associated NOTCH1 activation was implicated in
defective remyelination in MS, the precise mechanism by which NOTCH1 was engaged during inflammatory
response remains elusive. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS,
we and others have established that IL-17 signaling is crucial for the induction of inflammation in the CNS. We
have now discovered a direct integration of IL-17 and NOTCH1 signaling that plays a dominant role in impairing
the differentiation of OPCs. IL-17 stimulation induced the release of the intracellular domain of NOTCH1 (NICD1)
in the OPCs co-cultured with astrocytes. Mechanistically, IL-17R interacts with NOTCH1 via the extracellular
domain, which facilitates the cleavage of NICD1. Subsequently, Act1, the adaptor protein for IL-17 signaling,
forms a complex with NICD1, followed by translocation of Act1-NICD1 complex into the nucleus. Act1-NICD1
complex promotes the assembly of RBP-J containing transcriptional complex on the promoters of NOTCH1
target genes implicated in CNS inflammation. Furthermore, a decoy peptide disrupting the IL-17RA–NOTCH1
interaction inhibited IL-17-induced NICD cleavage, reduced IL-17-induced OPC prolifereation and attenuated
the myelin loss in EAE model. Based on these findings, we hypothesize IL-17-NOTCH1 pathway drives the
expression of a specific set of genes to promote inflammation and inhibition of OPC differentiation, thereby
impairing the remyelination process in the demyelinating disease. We will test this hypothesis through Aim 1:
Investigate the molecular mechanism of the inhibitory role of IL-17-NOTCH1 integration on OPC differentiation.
Aim 2: Investigate the in vivo impact of IL-17-NOTCH1 integration on remyelination process. The completion of
this proposal will provide fundamental insight into the critical integration of signaling pathways of IL-17 and
NOTCH1, which underlies the pathogenesis of demyelinating disease, offering novel therapeutic strategies for
MS patients by promoting remyelination.

## Key facts

- **NIH application ID:** 9870968
- **Project number:** 5R01NS104164-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Zizhen Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,458
- **Award type:** 5
- **Project period:** 2018-05-15 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870968

## Citation

> US National Institutes of Health, RePORTER application 9870968, The integration of IL-17 and NOTCH signaling in the pathogenesis of CNS inflammation (5R01NS104164-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870968. Licensed CC0.

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