Galectin-3, a rising star in modulating microglia activation under conditions of neurodegeneration

Abstract

The advent of high-throughput single-cell transcriptomic analysis of microglia has revealed different phenotypes that are inherently associated with disease conditions. A common feature of some of these activated phenotypes is the upregulation of galectin-3. Representative examples of these phenotypes include disease-associated microglia (DAM) and white-associated microglia (WAM), whose role(s) in neuroprotection/neurotoxicity is a matter of high interest in the microglia community. In this review, we summarise the main findings that demonstrate the ability of galectin-3 to interact with key pattern recognition receptors, including, among others, TLR4 and TREM2 and the importance of galectin-3 in the regulation of microglia activation. Finally, we discuss increasing evidence supporting the involvement of this lectin in the main neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, and stroke.

Fig. 1. Illustration from Burguillos et al. 2015 [31]: Gal-3 acts as a ligand to TLR4.

Left panel: Colocalisation of Gal-3 and TLR4 in BV2 cells after 1 h exposure with sGal-3 protein. Right panel: Microscale thermophoresis was used to analyse the direct binding of TLR4 to Gal-3, Gal-3 CRD, Gal-3 R186S, and Gal-3 in the presence of inhibitory lactose (40 mM). Whereas the concentration of fluorescently labelled TLR4 was kept constant, the non-labelled proteins were titrated (x axis), and the minimal and maximal Fnorm values of the unbound and bound state of TLR4, respectively, were used to calculate the percent of TLR4 bound to Gal-3 (y axis).

Fig. 2. Illustration from Boza-Serrano et al. 2019 [13]: Gal-3 interacts with TREM2.

Left panel: Gal-3 and TREM2 in plaque-associated microglia in the brain of 5xFAD mice reveal colocalisation of Gal-3 and TREM2. Right panel: Gal-3 and TREM2 interaction in 5xFAD mouse brain using Stochastic Optical Reconstruction Microscopy (STORM). All images were taken in 5xFAD mice at 18 months.

Fig. 3. Illustration from Yip et al. 2017 [14]: effect of the lack of galectin-3 on the neuronal survival in cortex and hippocampus after TBI.

Representative pictures of NeuN in different regions (left panel). Representative image of toluidine blue staining in wild-type and galectin-3 knockout mice (right panel). Note neuroprotection at 24 h and limited injury size 21 days after the TBI in Gal-3 KO mice. Scale bars are 100 and 1000 µm respectively.

Fig. 4. Broad view of the role of Galectin-3 in microglia-associated neurodegenerative diseases.

Galectin-3 (Gal-3) is one of the most highly expressed in Alzheimer’s Disease (AD) associated microglia (DAM) interacting with TREM2, TLR4 and MERTK. White matter-associated microglia (WAM) is also triggered by TREM2 activity but no role for Gal-3 has been yet uncovered. Gal-3 is found in the outer layer of the Lewy Bodies in neurons from Parkinson’s Disease (PD) patients, whereas internalisation of alpha-synuclein (αS) by microglia leads to the release of Gal-3 to the extracellular matrix. In Huntington’s Disease (HD) Gal-3 is known to be released by microglia leading to inflammasome pathway activation and cytokine release. In Multiple Sclerosis (MS) Gal-3 is released in response to demyelinization and known to interact with TREM2. In Amyotrophic Lateral Sclerosis (ALS) microglia release Gal-3 which exerts a neuroprotective role, but no mechanism nor ligands have been identified. In Stroke, Gal-3 present a dual role binding to TLR4 and IGF1R to increase cytokine production and microgliosis, but also promoting VEGF release and angiogenesis. In Traumatic Brain Injury (TBI), Gal-3 is highly released after the trauma and binds to TLR4 predominantly to promote an intense inflammatory reaction associated to cytokine release.