Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis
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Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.
KeywordsCanonical WNT/beta-catenin pathway PPAR gamma Multiple sclerosis PI3K/Akt pathway Demyelination Remyelination Inflammation TCF7L2
Adenomatous polyposis coli
Glycogen synthase kinase-3beta
- LRP 5/6
Low-density lipoprotein receptor-related protein 5/6
Phosphatidylinositol 3-kinase-protein kinase B
- PPAR gamma
Peroxisome proliferator-activated receptor gamma
T cell factor/lymphoid enhancer factor
We would like to thank Dr Christophe Locher, President of the “Fédération de la Recherche Clinique du Grand Hôpital de l’Est Francilien,” and Mr. Vincent Gobert, Administrative Manager of the Clinical Research Center, Meaux Hospital, Meaux, France, for their valuable support in making the necessary research facilities available for this study.
All authors listed, have made substantial, direct, and intellectual contribution to the work, and approved it for publication. AV, JNV, RG, and YL have contributed to this review.
Compliance with Ethical Standards
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial, financial relationship, or non-financial interest that could be construed as a potential conflict of interest.
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