Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function

Abstract

Galectins control critical pathophysiological processes, including the progression and resolution of central nervous system (CNS) inflammation. In spite of considerable progress in dissecting their role within lymphoid organs, their functions within the inflamed CNS remain elusive. Here, we investigated the role of galectin-glycan interactions in the control of oligodendrocyte (OLG) differentiation, myelin integrity and function. Both galectin-1 and -3 were abundant in astrocytes and microglia. Although galectin-1 was abundant in immature but not in differentiated OLGs, galectin-3 was upregulated during OLG differentiation. Biochemical analysis revealed increased activity of metalloproteinases responsible for cleaving galectin-3 during OLG differentiation and modulating its biological activity. Exposure to galectin-3 promoted OLG differentiation in a dose- and carbohydrate-dependent fashion consistent with the 'glycosylation signature' of immature versus differentiated OLG. Accordingly, conditioned media from galectin-3-expressing, but not galectin-3-deficient (Lgals3(-/-)) microglia, successfully promoted OLG differentiation. Supporting these findings, morphometric analysis showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio in the corpus callosum and striatum of Lgals3(-/-) compared with wild-type (WT) mice. Moreover, the myelin structure was loosely wrapped around the axons and less smooth in Lgals3(-/-) mice versus WT mice. Behavior analysis revealed decreased anxiety in Lgals3(-/-) mice similar to that observed during early demyelination induced by cuprizone intoxication. Finally, commitment toward the oligodendroglial fate was favored in neurospheres isolated from WT but not Lgals3(-/-) mice. Hence, glial-derived galectin-3, but not galectin-1, promotes OLG differentiation, thus contributing to myelin integrity and function with critical implications in the recovery of inflammatory demyelinating disorders.

Galectin-3 Is Required for Resident Microglia Activation and Proliferation in Response to Ischemic Injury

“…While previous studies reported that galectin-3 is required for the recognition of pathogenassociated molecular patterns (PAMPs) to TLRs (DebierreGrockiego et al, 2010), our results for the first time showed that galectin-3 may also be required for proper induction of the innate immune response after ischemic injury. Although at this time the effects of galectin-3 on other cells types should not be neglected and/or excluded (Pasquini et al, 2011), our results suggest that early after stroke galectin-3 may represent a major immunomodulatory molecule that coordinates processes of injury-induced microglial activation and proliferation. Namely, the results of our present study revealed that galectin-3 deficiency was associated with a marked deregulation of the IGF-1 system responses to injury as well as the inability of Gal-3 KO microglial cells to proliferate in response to IGF-1-mediated mitogenic signals (Figs.…”

“…Recent evidence obtained from Gal-3KO suggests that galectin-3 may have a role in the oligodendrocyte differentiation and the control of myelin integrity (Pasquini et al, 2011). Furthermore, studies from Compte et al (2011) reported potential role of galectin-3 in the modulation of cell motility in the rostral migratory stream.…”

Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro

“…Expression of these markers is consistent with a repair/reparatory phenotype, as CD206 is a mannose receptor which stimulates phagocytosis (Zimmer et al, 2003); IGF-1 is a cytoprotective growth factor (Johnston et al, 1996); Arg1s catalytic activity produces polyamines that support extracellular matrix repair and mitochondrial function (Pesce et al, 2009); and Gal-3 is a modulator of proliferation (Inohara et al, 1998), and oligodendrocyte maturation and remyelination (Pasquini et al, 2011). Within this model system, increased Arg1 was the only marker able to positively discriminate an M2a phenotype at all time points.…”

Ligand-mediated Galectin-1 endocytosis prevents intraneural H2O2 production promoting F-actin dynamics reactivation and axonal re-growth

“…Spinal cords were removed and post-fixed overnight (ON) in the same fixative solution, then treated with a sucrose gradient (15 to 30%) and washed with PBS. Tissue was then frozen to obtain 30-μm cryostat longitudinal (cranial to caudal and dorso to ventral) sections using a Leica CM 1850 cryotome (Pasquini et al, 2011). To perform the analysis, 11 serial sections of spinal cord were collected from each specimen (vehicle control vs wt-Gal-1) and, using a free floating technique, the immunohistochemistry was carried out for a particular antigen or antigen pair as previously described by (Katherine Zukor,1 Stephane Belin,1 Chen Wang,1 Nadia Keelan,1,2 Xuhua Wang,1 and Zhigang He1).…”