Galectin-3 alleviates demyelination by modulating microglial anti-inflammatory polarization through PPARγ-CD36 axis.

Demyelination is characterized by disruption of myelin sheath and disorders in myelin formation. Currently, there are no effective therapeutic treatments available. Microglia, especially anti-inflammatory phenotype microglia are critical for remyelination. Galectin-3 (Gal-3), which is known to modulate microglia activation, is correlated with myelination. In this study, we aimed to elucidate the roles of Gal-3 during myelin formation and explore the efficiency and mechanism of rGal-3 administration in remyelination. We enrolled Gal-3 knockout (Lgals3 KO) mice and demonstrated Lgals3 KO causes demyelination during spontaneous myelinogenesis. We performed a cuprizone (CPZ) intoxication model and found Lgals3 KO aggravates demyelinated lesions and favors microglial pro-inflammatory phenotype polarization. Recombinant Gal-3 (rGal-3) administration alleviates CPZ intoxication and drives microglial towards anti-inflammatory phenotype. Additionally, RNA sequencing results reveal the correlation between Gal-3 and the PPARγ-CD36 axis. Thus, we performed SSO and GW9662 administration to inhibit the activation of the PPARγ-CD36 axis and found that rGal-3 administration modulates microglial phenotype polarization by regulating the PPARγ-CD36 axis. Together, our findings highlight the importance of Gal-3 in myelination and provide insights into rGal-3 administration for modulating microglial anti-inflammatory phenotype polarization through the PPARγ-CD36 axis.

Wang Q ，Zeng F ，Fang C ，Sun Y ，Zhao X ，Rong X ，Zhang H ，Xu Y ... -  《-》

Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination.

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that plays an important role in inflammatory and neurodegenerative diseases. Cuprizone (CPZ)-induced demyelination is characterized by the loss of mature oligodendrocytes (OLG) by apoptosis, myelin sheath degeneration and recruitment of microglia and astrocytes to the lesioned area. We compared CPZ-induced demyelination of 8-week-old Lgals3(-/-) vs WT mice. Lgals3(-/-) mice displayed a similar susceptibility to CPZ-induced demyelination up to the fifth week, as evaluated by MBP immunostaining and electronic microscopy. However, OLG progenitors (OPC) generated in CPZ-treated Lgals3(-/-) mice showed diminished arborization, suggesting decreased ability of these cells to differentiate. Surprisingly, while WT mice experienced spontaneous remyelination in the fifth week of CPZ treatment-even though the CPZ diet was maintained up to sixth week-Lgals3(-/-) mice lacked this capacity and suffered continuous demyelination up to the sixth week, accompanied by pronounced astroglial activation. Moreover, after 2weeks of CPZ treatment, WT and Lgals3(-/-) mice showed lower innate anxiety as compared with respective naive mice, but only CPZ-treated Lgals3(-/-) mice showed decreased locomotor activity and exhibited spatial working memory impairment. Expression of Gal-3 increased during CPZ-induced demyelination in microglia but not in astrocytes. While CPZ-treated WT mice displayed heightened microglial activation associated with ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effect was not observed in CPZ-treated Lgals3(-/-) mice which, in spite of showing an increased number of microglia, these cells evidenced caspase-3 activation. Our results indicate that Gal-3 is expressed in microglial cells to modulate their phenotype, facilitating the onset of remyelination and OLG differentiation.

Hoyos HC ，Rinaldi M ，Mendez-Huergo SP ，Marder M ，Rabinovich GA ，Pasquini JM ，Pasquini LA ... -  《-》

The Role of Galectin-3: From Oligodendroglial Differentiation and Myelination to Demyelination and Remyelination Processes in a Cuprizone-Induced Demyelination Model.

Hoyos HC ，Marder M ，Ulrich R ，Gudi V ，Stangel M ，Rabinovich GA ，Pasquini LA ，Pasquini JM ... -  《Advances in Experimental Medicine and Biology》

The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis.

In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site of demyelination by microglia is critically important to achieve adequate remyelination and to slow the progression of the disease. However, how microglia phagocytose the myelin debris, and why clearance is impaired in MS, is not fully known; likewise, the role of the microglia in remyelination remains unclear. Recent studies using cuprizone (CPZ) as an animal model of central nervous system demyelination revealed that the up-regulation of signaling proteins in microglia facilitates effective phagocytosis of myelin debris. Moreover, during demyelination, protective mediators are released from activated microglia, resulting in the acceleration of remyelination in the CPZ model. In contrast, inadequate microglial activation or recruitment to the site of demyelination, and the production of toxic mediators, impairs remyelination resulting in progressive demyelination. In addition to the microglia-mediated phagocytosis, astrocytes play an important role in the phagocytic process by recruiting microglia to the site of demyelination and producing regenerative mediators. The current review is an update of these emerging findings from the CPZ animal model, discussing the roles of microglia and astrocytes in phagocytosis and myelination.

Sen MK ，Mahns DA ，Coorssen JR ，Shortland PJ ... -  《-》

The Spatial and Temporal Characters of Demyelination and Remyelination in the Cuprizone Animal Model.

Multiple sclerosis (MS) is the most common central nervous system disease due to demyelination in young adults, and currently, there is no cure. Some experimental animal models were generated to mimic specific aspects of MS pathological characteristics. Among them, the cuprizone (CPZ)-induced mouse demyelination model presents heterogeneous pathologies with both focal and diffuse lesions. Considering that MS is a progressive disease, it is important to study the spatial and temporal characters of de- and remyelination in MS animal models. However, such data especially in some brain regions such as lateral septal area, fimbria of hippocampus, and hippocampus are still lacking. In this study, we investigated the alterations of myelin in these areas in parallel to the changes in corpus callosum using coronal sections. We found that the progression of demyelinating varied in different brain regions in C57BL/6J mice treated with CPZ for 1 to 5 weeks. This result suggests that each brain region has a distinct sensitivity to CPZ intoxication. Interestingly, activated microglia appeared not only in the active demyelinating areas but also in the non-myelinolysis regions. After CPZ withdrawal, significant remyelination was started in corpus callosum as early as 3 days. The completion of remyelination in the entire brain regions took 3 weeks. Our study detailed characterized the dynamics of myelin alterations and microglial status in the brain of the CPZ model. This information is valuable to facilitate further MS studies utilizing the CPZ model. Anat Rec, 302:2020-2029, 2019. © 2019 American Association for Anatomy.

Zhang Y ，Cai L ，Fan K ，Fan B ，Li N ，Gao W ，Yang X ，Ma J ... -  《-》