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Updated: Feb 19, 2026
Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
Published on: September 4, 2013
Galectin-3 mediates lysosome-related inflammation within monocyte-derived macrophages in a mouse model of ischemic
Miao Wang1,2, Zhentai Huang1,2, Zhihong Du2
1Geriatric Research Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA.
Abstract:
Circulating monocyte-derived macrophages (MDMø) rapidly invade the brain after stroke, exerting both detrimental and beneficial effects. Elucidating mechanisms that mediate detrimental properties of MDMø may identify therapeutic strategies to divert MDMø from destructive phenotypes, while preserving their favorable effects. Toward this goal, the current study explores the function of Galectin-3 (GAL3) in MDMø and elucidates mechanisms whereby MDMø-derived GAL3 exacerbates stroke injury. In the acutely injured brain, GAL3 expression was upregulated primarily within MDMø. Global KO of GAL3 reduced brain infarcts in the short term but did not sustain long-term positive outcomes. Using BM chimera mice, macrophage transplantation, and myeloid cell-specific GAL3-KO (LysMCre+/-Lgals3fl/fl) mice, we demonstrated that GAL3 in MDMø mediated acute infarct expansion after stroke. Coculturing brain lysate-treated, BM-derived macrophages (BMDMs) with oxygen glucose deprivation-challenged neurons induced neurotoxicity that was mitigated by the cell-permeable, selective GAL3 inhibitor TD139. GAL3 triggered cathepsin induction and lysosomal leakage in BMDMs, leading to inflammasome activation. Systemic and transient TD139 treatment in the acute injury phase reduced infarcts, tempered neuroinflammation, and improved long-term neurological outcomes. Therefore, MDMø-derived GAL3 represents a drug target that could be accessed in peripheral blood to potentially mitigate post-stroke brain injury.
Insights
Galectin-3 in monocyte-derived macrophages exacerbates stroke injury by promoting neuroinflammation. Inhibiting Galectin-3 in the acute phase reduces brain damage and improves long-term outcomes after stroke.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Monocyte-derived macrophages (MDMø) infiltrate the brain post-stroke, with dual roles.
- Understanding detrimental MDMø mechanisms is key for stroke therapeutics.
- Galectin-3 (GAL3) is explored for its role in MDMø-mediated stroke injury.
Purpose of the Study:
- To investigate the function of Galectin-3 (GAL3) in monocyte-derived macrophages (MDMø).
- To elucidate mechanisms by which MDMø-derived GAL3 worsens stroke injury.
- To assess the therapeutic potential of targeting GAL3 in stroke.
Main Methods:
- Utilized global GAL3 knockout and myeloid cell-specific GAL3 knockout mice.
- Employed bone marrow chimeras and macrophage transplantation models.
- Investigated neurotoxicity using co-cultures and treated with GAL3 inhibitor TD139.
Main Results:
- GAL3 expression was upregulated in brain MDMø post-stroke.
- MDMø-derived GAL3 mediated acute infarct expansion.
- TD139 treatment reduced infarcts, neuroinflammation, and improved neurological outcomes.
Conclusions:
- MDMø-derived GAL3 exacerbates acute stroke injury.
- GAL3 triggers cathepsin induction, lysosomal leakage, and inflammasome activation.
- Targeting peripheral GAL3 offers a potential therapeutic strategy for stroke.
