Galectin-3 worsens microglia-mediated synaptic engulfment and neuroinflammatory responses after traumatic brain injury

Abstract

Activated microglia-mediated aberrant synaptic phagocytosis is an important contributor to neurological deficits following traumatic brain injury (TBI). Galectin-3 (Gal-3), a pivotal regulator of microglial activity, is increased after TBI. However, its role in microglia-mediated synaptic phagocytosis and associated neuroinflammation remains unclear. Microglial phagocytic activity post-TBI was analyzed using public single-cell RNA sequencing datasets from GEO. The function of Gal-3 was investigated in a mouse model of controlled cortical impact by intraperitoneal administration of the selective inhibitor TD139. Sensorimotor and cognitive functions, microglial heterogeneity, synaptic engulfment, and neuroinflammation were assessed using behavioral tests, immunostaining, western blotting, and RT-qPCR. Gal-3 expression was specifically upregulated in phagocytic microglia following TBI. Pharmacological inhibition of Gal-3 by TD139 alleviated long-term sensorimotor and cognitive dysfunction and reduced cerebral tissue loss. Additionally, TD139 treatment promoted microglial heterogeneity, elevated the expression of anti-inflammatory factors, and inhibited excessive microglial synaptic engulfment, thereby attenuating synapse loss and preserving synaptic integrity. Microglial Gal-3 drives neuroinflammation and aberrant synaptic phagocytosis, contributing to neurological deficits following TBI. These findings identify Gal-3 as a promising therapeutic target for TBI intervention.