Galectin-3 mediates lysosome-related inflammation within monocyte-derived macrophages in a mouse model of ischemic brain injury
Miao Wang, Zhentai Huang, Zhihong Du, Jiajing Shan, Qing Ye, Lingxiao Lu, Ming Jiang, Fei Xu, Ziyang Liu, David J.R. Fulton, Rehana K. Leak, Babak Razani, Jun Chen, Xiaoming Hu
Miao Wang, Zhentai Huang, Zhihong Du, Jiajing Shan, Qing Ye, Lingxiao Lu, Ming Jiang, Fei Xu, Ziyang Liu, David J.R. Fulton, Rehana K. Leak, Babak Razani, Jun Chen, Xiaoming Hu
View: Text | PDF
Research Article Inflammation Neuroscience

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

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.

Authors

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

×

Figure 2

GAL3 KO reduces brain infarct in the early injury phase but does not improve neurological outcomes in the chronic injury phase after stroke.

Options: View larger image (or click on image) Download as PowerPoint
GAL3 KO reduces brain infarct in the early injury phase but does not imp...
WT and GAL3-KO mice were subjected to 60 min tMCAO. (A) Representative Nissl staining and quantification of brain infarct 3 d after tMCAO. N = 10–12/group. The red dashed lines trace the border of infarct lesion. (B) Representative MAP2 staining and quantification of brain atrophy 7 d after tMCAO. N = 7–8/group. The red dashed lines trace the border of infarct lesion. (C and D) Sensorimotor function was assessed using the rotarod (C) and foot fault (D) tests. (E–G) Cognitive function was assessed using the Morris water maze test. (E) The latencies to locate the escape platform during the learning phase. (F) Time spent in the target quadrant where the escape platform was previously located during the memory probe test. (G) Average swim speed across the test phase. (H) Representative MAP2 staining and quantification of brain atrophy 28 d after tMCAO. The areas of contralesional hemisphere are reflected on the ipsilesional hemisphere (red dashed lines). N = 11/group for C–H. *P < 0.05. Two-tailed, unpaired Student’s t test (A, B, F, G, and H) and 2-way repeated measures ANOVA and Bonferroni’s test (C–E).