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
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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

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Figure 8

Transient GAL3 inhibition improves long-term stroke outcomes.

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Transient GAL3 inhibition improves long-term stroke outcomes. (A) Experi...
(A) Experimental design. (B) Representative images of T2 MRI scans. For tMCAO 3d, the yellow dashed lines trace the border of infarct lesion. For tMCAO 14d, the areas of contralesional hemisphere are reflected on the ipsilesional hemisphere (yellow dashed lines). (C and D) Quantification of T2 signals revealed brain infarcts (C) and brain edema (D). N = 8/group. (E and F) Motor abilities were assessed using rotarod (E) and foot fault (F) tests. N = 8/group. (G–J) Cognitive performance was assessed using the Morris water maze. N = 8/group. (G) Representative swimming trace during learning and memory tests. Small circles show the position of the platform. (H) The latencies of finding the escape platform during the learning phase. (I) Time spent in the target quadrant where platform was previously located during the learning phase. (J) Average swimming speed. (K) Analysis of Pearson’s correlation between the average latency to fall on the rotarod test (days 7–28) and tissue loss measured 3 d after MCAO. (L) Analysis of Pearson’s correlation between the average escape latency in the water maze test (days 24–25) and tissue loss measured 3 d after MCAO. (M) 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 = 5/group. (N) PCR analysis of mRNA expression of Il-1b, Tnfa, Ifng, and Il-6. Data are expressed as percentages of contralateral levels. N = 3/group. (O) Flow cytometry detected the number of GAL3+CD11b+ monocytes 28 d after tMCAO in the blood of young WT mice treated with vehicle or TD139. N = 8/group. *P < 0.05, **P < 0.01, ***P < 0.001. Two-tailed, unpaired Student’s t test (D, I, J, M, N, and O), 2-way ANOVA (C), or 2-way repeated measures ANOVA (E, F, and H) and Bonferroni’s test.