Galectin-9 mediates microglial cell death in brain tumor microenvironment

Galectin-9 (Gal-9) is a tandem-repeat type member of β-galactoside binding lectins expressed in various immune cells. Gal-9 has been identified as an apoptotic inducer and a suppressor of T cells via binding to T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3). However, the role of Gal-9 in myeloid lineage cells, especially in microglia during the brain pathologies, remains unclear. Here, we report the functional properties of Gal-9 on microglia within the brain tumor microenvironment. We showed that Gal-9 is significantly upregulated in microglia after exposure to GL26 glioma, while Tim-3 is decreased under the same condition. We further found that Gal-9⁺ microglia exhibit higher cell death than Gal-9^– microglia. To examine whether the Gal-9-related microglial cell death is associated with Gal-9/Tim-3 interaction, we compared the cell death of Gal-9⁺Tim-3^– and Gal-9⁺Tim-3⁺ microglia. Interestingly, we found that the apoptotic cell death in Gal-9⁺Tim-3^– microglia is significantly higher than that in Gal-9⁺Tim-3⁺ microglia. Furthermore, the percentage of apoptotic cells was increased in Tim-3 knock-out microglia compared to that in wild type microglia, suggesting that loss of Tim-3 contributes to the galectin-9-mediated microglial cell death. Taken together, our data suggest that Gal-9 may play a crucial role in cell death of microglia in brain tumor microenvironment, thereby affecting tumor immunity.