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Galectin-3 mediates lysosome-related inflammation within monocyte-derived macrophages in a mouse model of ischemic brain injury

Miao Wang,¹ Zhentai Huang,¹ Zhihong Du,¹ Jiajing Shan,¹ Qing Ye,¹ Lingxiao Lu,¹ Ming Jiang,¹ Fei Xu,¹ Ziyang Liu,² David J.R. Fulton,³ Rehana K. Leak,⁴ Babak Razani,² Jun Chen,¹ and Xiaoming Hu¹

Published February 17, 2026 - More info

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 knockout of GAL3 reduced brain infarcts in the short-term but did not sustain long-term positive outcomes. Using bone marrow chimera mice, macrophage transplantation, and myeloid cell-specific GAL3 knockout (LysMCre^+/–Lgals3^f/f) mice, we demonstrated that GAL3 in MDMø mediated acute infarct expansion after stroke. Coculturing brain lysate-treated bone marrow-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.

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