Galectin-3 activates microglia and promotes neurological impairment via NLRP3/pyroptosis pathway following traumatic brain injury

  • Brain Res. 2025 Mar 10:1855:149560. doi: 10.1016/j.brainres.2025.149560.
Yan Sun  1 ,  Sheng-Qing Gao  2 ,  Xue Wang  2 ,  Tao Li  1 ,  Yan-Ling Han  2 ,  Shu-Hao Miao  1 ,  Ran Zhao  2 ,  Xiao-Bo Zheng  3 ,  Jia-Yin Qiu  2 ,  Wang-Xuan Jin  2 ,  Chao-Chao Gao  1 ,  Meng-Liang Zhou  4
Affiliations
  • 1. Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 2. Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 3. Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing. China.
  • 4. Department of Neurosurgery, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, China; Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. Electronic address: [email protected].
PMID: 40074166 DOI: 10.1016/j.brainres.2025.149560
Abstract

Background: Externally caused traumatic brain injury (TBI) poses a woeful worldwide health concern, bringing about disability, death, and prolonged neurological impairment. Increased Galectin-3 levels have been linked to unfavorable outcomes in several neurological conditions. This study explores the role of Galectin-3 in TBI, specifically examining its contribution to neuroinflammation.

Methods: BV2 microglia cells treated with lipopolysaccharide (LPS) and a mouse model of TBI were applied to investigate the impact of Galectin-3 on neuroinflammation following TBI. Western blotting and immunofluorescence labeling were applied for evaluating protein levels and colocalization. Adeno-associated virus (AAV) that targets microglia was used to knock down Galectin-3 in microglia. Nissl staining and the modified neurologic severity score were employed in evaluating neural survival and neurological function, and the cognitive impairment following TBI was assessed by the Y-Maze and Morri water maze test.

Results: Galectin-3 expression was shown to rise dramatically after TBI, peaking between days five and seven. In vitro, BV2 cells treated with LPS showed reduced NOD-like Receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation when Galectin-3 was inhibited. In LPS-activated microglia, Galectin-3 inhibition specifically decreased the expression of Toll-like Receptor 4 (TLR4), nuclear factor-κB (NF-κB), p-NF-κB, NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, and Gasdermin D (GSDMD). Injection with AAV containing siRNA to knock down Galectin-3 in microglia was operated on mice in vivo. Following TBI, this knockdown led to reduced NLRP3 inflammasome activation, neuronal death, neurological impairments and cognitive impairment.

Conclusions: Our foundings indicate that modulating microglia-derived Galectin-3 following TBI to reduce neuroinflammation could serve as a promising therapeutic strategy.

Keywords
Galectin-3; Microglia; NLRP3 inflammasome; Neuroinflammation; Traumatic brain injury.
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