Centre de Recherche du Centre Hospitalier de l'Université Laval, Quebec City, Quebec G1V 4G2, Canada.
J Neurosci. 2012 Jul 25;32(30):10383-95. doi: 10.1523/JNEUROSCI.1498-12.2012.
Growing evidence suggests that galectin-3 is involved in fine tuning of the inflammatory responses at the periphery, however, its role in injured brain is far less clear. Our previous work demonstrated upregulation and coexpression of galectin-3 and IGF-1 in a subset of activated/proliferating microglial cells after stroke. Here, we tested the hypothesis that galectin-3 plays a pivotal role in mediating injury-induced microglial activation and proliferation. By using a galectin-3 knock-out mouse (Gal-3KO), we demonstrated that targeted disruption of the galectin-3 gene significantly alters microglia activation and induces ∼4-fold decrease in microglia proliferation. Defective microglia activation/proliferation was further associated with significant increase in the size of ischemic lesion, ∼2-fold increase in the number of apoptotic neurons, and a marked deregulation of the IGF-1 levels. Next, our results revealed that contrary to WT cells, the Gal3-KO microglia failed to proliferate in response to IGF-1. Moreover, the IGF-1-mediated mitogenic microglia response was reduced by N-glycosylation inhibitor tunicamycine while coimmunoprecipitation experiments revealed galectin-3 binding to IGF-receptor 1 (R1), thus suggesting that interaction of galectin-3 with the N-linked glycans of receptors for growth factors is involved in IGF-R1 signaling. While the canonical IGF-1 signaling pathways were not affected, we observed an overexpression of IL-6 and SOCS3, suggesting an overactivation of JAK/STAT3, a shared signaling pathway for IGF-1/IL-6. Together, our findings suggest that galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury.
越来越多的证据表明，半乳糖凝集素-3 参与外周炎症反应的微调，但其在受损大脑中的作用还远不明确。我们之前的工作表明，在中风后，半乳糖凝集素-3 和 IGF-1 在一小部分激活/增殖的小胶质细胞中上调和共表达。在这里，我们检验了这样一个假设，即半乳糖凝集素-3 在介导损伤诱导的小胶质细胞激活和增殖中起着关键作用。通过使用半乳糖凝集素-3 敲除小鼠（Gal-3KO），我们证明了半乳糖凝集素-3 基因的靶向敲除显著改变了小胶质细胞的激活，并诱导小胶质细胞增殖减少约 4 倍。小胶质细胞激活/增殖的缺陷与缺血性病变的大小显著增加有关，凋亡神经元的数量增加了约 2 倍，IGF-1 水平的明显失调。接下来，我们的结果表明，与 WT 细胞相反，Gal3-KO 小胶质细胞未能对 IGF-1 增殖。此外，N-糖基化抑制剂他莫西环素降低了 IGF-1 介导的促有丝分裂小胶质细胞反应，而共免疫沉淀实验表明半乳糖凝集素-3 与 IGF-受体 1（R1）结合，因此表明半乳糖凝集素-3 与生长因子受体的 N-连接聚糖的相互作用参与 IGF-R1 信号传导。虽然经典的 IGF-1 信号通路不受影响，但我们观察到 IL-6 和 SOCS3 的过度表达，这表明 JAK/STAT3 的过度激活，IGF-1/IL-6 的共同信号通路。总之，我们的研究结果表明，半乳糖凝集素-3 是缺血性损伤后常驻小胶质细胞激活和增殖所必需的。
