GALECTIN-8 Is a Neuroprotective Factor in the Brain that Can Be Neutralized by Human Autoantibodies

• DOI: 10.1007/s12035-019-1621-3
• Publication Date: 2019-05-23T01:13:49Z
• Authors: Evelyn Pardo; Francisca Barake; Juan A. Godoy; Claudia Oyanadel; Sofía Espinoza; Claudia Metz; Claudio Retamal; Loreto Massardo; Cheril Tapia-Rojas; Nibaldo C. Inestrosa; Andrea Soza; Alfonso González
• Keywords: 0301 basic medicine; Cell Survival; Galectins; Cerebro - Metabolismo; 610; Apoptosis; Hippocampus; Rats, Sprague-Dawley; 03 medical and health sciences; Animals; Humans; Autoanticuerpos - Farmacología; Extracellular Signal-Regulated MAP Kinases; Autoantibodies; Neurons; Galectinas; Integrin beta1; Brain; Hydrogen Peroxide; Antibodies, Neutralizing; Neuroprotection; 3. Good health; Medicina y salud; Proto-Oncogene Proteins c-akt; Protein Binding; Signal Transduction

Galectin-8 (Gal-8) is a glycan-binding protein that modulates a variety of cellular processes interacting with cell surface glycoproteins. Neutralizing anti-Gal-8 antibodies that block Gal-8 functions have been described in autoimmune and inflammatory disorders, likely playing pathogenic roles. In the brain, Gal-8 is highly expressed in the choroid plexus and accordingly has been detected in human cerebrospinal fluid. It protects against central nervous system autoimmune damage through its immune-suppressive potential. Whether Gal-8 plays a direct role upon neurons remains unknown. Here, we show that Gal-8 protects hippocampal neurons in primary culture against damaging conditions such as nutrient deprivation, glutamate-induced excitotoxicity, hydrogen peroxide (H2O2)-induced oxidative stress, and β-amyloid oligomers (Aβo). This protective action is manifested even after 2 h of exposure to the harmful condition. Pull-down assays demonstrate binding of Gal-8 to selected β1-integrins, including α3 and α5β1. Furthermore, Gal-8 activates β1-integrins, ERK1/2, and PI3K/AKT signaling pathways that mediate neuroprotection. Hippocampal neurons in primary culture produce and secrete Gal-8, and their survival decreases upon incubation with human function-blocking Gal-8 autoantibodies obtained from lupus patients. Despite the low levels of Gal-8 expression detected by real-time PCR in hippocampus, compared with other brain regions, the complete lack of Gal-8 in Gal-8 KO mice determines higher levels of apoptosis upon H2O2 stereotaxic injection in this region. Therefore, endogenous Gal-8 likely contributes to generate a neuroprotective environment in the brain, which might be eventually counteracted by human function-blocking autoantibodies.