Induction of immunoregulatory microglia by the Wnt pathway during neuroinflammation

Project: Research project

Project Details

Description

Title:
Induction of immunoregulatory microglia by the Wnt pathway during neuroinflammation
It has been suggested that a change in microglia phenotype towards an
immunoregulatory profile is critical for proper remyelination during
neuroinflammation. However the mechanism leading to this change of phenotype
during central nervous system (CNS) inflammation remains unknown. On peripheral
myeloid cells, activation of the Wnt/beta-catenin pathway induces an
immunoregulatory phenotype, characterized by upregulation of the
immunoregulatory molecules PD-L1 and PD-L2, increased levels of pSTAT1 and
pSTAT3, as well as downregulation of IL-1b, IL-6, IL-12 and IL-23. Additionally,
treatment of mice undergoing experimental allergic encephalomyelitis (EAE), a
mouse model of multiple sclerosis (MS) with the Wnt agonist significantly reduces
the severity of the disease. Thus activation of the Wnt pathway appears to be part of
a regulatory mechanism leading to the resolution of inflammation, which in MS could
be partly responsible for the remission phase observed in RR-MS patients. Wnt
proteins are naturally expressed in the CNS by brain endothelial cells and
astrocytes. Moreover, during CNS inflammation, brain endothelial cells and
astrocytes upregulate their levels of Wnt expression while microglia upregulate their
expression of Wnt receptor, Fzd. We thus hypothesized that activation of this
pathway in microglia lead to a change of phenotype necessary for proper
remyelination. To address this hypothesis, I propose the following 2 aims: 1)
Characterize the expression of Wnt signaling pathway molecules in microglia during
homeostasis and neuroinflammation in the CNS; 2) Evaluate the effect of the
Wnt/beta-catenin pathway activation on resting microglia, during CNS inflammation,
and after demyelinating events. This project proposes to evaluate the effects of Wnt
pathway activation and blockade on microglia specifically, and on the capacity of
Wnt-activated microglia to contribute to remyelination. Overall, this study will
enhance our understanding on the molecular mechanism leading to the change of
phenotype of microglia during CNS inflammation as well as to begin to define novel
potential targets for the treatment of MS.
StatusActive
Effective start/end date10/1/199/30/20

Funding

  • National Multiple Sclerosis Society (PP-1905-33998)

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