Department of Medicine, Division of Allergy, Immunology & Rheumatology, 6074 UB's Clinical and Translational Research Center, State University of New York at Buffalo, 875 Ellicott St, Buffalo, NY, 14203, USA.
Department of Medicine, Division of Nephrology, UB Clinical and Translational Research Center, SUNY University at Buffalo, 875 Ellicott Street, Buffalo, NY, 14203, USA.
J Neuroimmune Pharmacol. 2017 Mar;12(1):133-151. doi: 10.1007/s11481-016-9723-4. Epub 2016 Dec 27.
Galectins are a family of β-galactoside-binding lectins that are important modulators of homeostasis in the central nervous system (CNS). Galectin-1 is a pivotal regulator of microglia activation that alters the immune balance from neurodegeneration to neuroprotection and could have therapeutic relevance in HIV associated neurocognitive disorders (HAND). We have previously shown that galectin-1 treatment decreased oxidative stress in microglia and hypothesize that the mechanism underlying this phenomenon is the cross regulatory interactions between Nitric oxide (NO) and Arginase I activity in microglia. We induced microglial activation and examined the effect of galectin-1 on the expression of various M1/M2 microglial phenotypic markers. Since, TNF-α is associated with activation of microglial cells involved in pathogenesis of neurodegenerative diseases, we treated HIV transfected human microglial cell cultures (CHME-5/HIV) with TNF-α followed by treatment with galectin-1, to examine the galectin-1 mediated neuro-modulatory response. Our results show that treatment of CHME-5/HIV microglia with galectin-1 reduced TNF-α induced oxidative stress by ~40%, and also significantly reduced iNOS gene expression and NO production while correspondingly increasing arginase-1, cationic amino acid transporter (CAT-1) gene expression and arginase activity. Galectin-1 treatment results in shifting microglia polarization from M1 toward the beneficial M2 phenotype which may prevent neurodegeneration and promote neuroprotection. Thus, our data suggests that galectin-1 treatment reduces neuroinflammation in the CNS microenvironment via the modulation of the NO-arginase network in microglia and thus could play a neuroprotective role in HAND. Further, the therapeutic potential of galectin-1 could be enhanced by conjugation of galectin-1 onto gold nanoparticles (Au-NP), resulting in a nanogold-galectin-1 (Au-Gal-1) multivalent complex that will have more clinical translational efficacy than free galectin-1 by virtue of increasing the payload influx.
半乳糖凝集素是一类β-半乳糖苷结合凝集素，是中枢神经系统（CNS）内稳态的重要调节剂。半乳糖凝集素-1 是小胶质细胞激活的关键调节因子，它改变了从神经退行性变到神经保护的免疫平衡，并且在 HIV 相关神经认知障碍（HAND）中可能具有治疗相关性。我们之前已经表明，半乳糖凝集素-1 治疗可降低小胶质细胞中的氧化应激，并且假设这种现象的机制是小胶质细胞中一氧化氮（NO）和精氨酸酶 I 活性的交叉调节相互作用。我们诱导小胶质细胞激活，并研究了半乳糖凝集素-1 对各种 M1/M2 小胶质细胞表型标志物表达的影响。由于 TNF-α 与涉及神经退行性疾病发病机制的小胶质细胞激活有关，因此我们用 TNF-α 处理 HIV 转染的人小胶质细胞培养物（CHME-5/HIV），然后用半乳糖凝集素-1 处理，以检查半乳糖凝集素-1 介导的神经调节反应。我们的结果表明，用半乳糖凝集素-1 处理 CHME-5/HIV 小胶质细胞可将 TNF-α诱导的氧化应激降低约 40％，同时还显著降低 iNOS 基因表达和 NO 产生，同时相应增加精氨酸酶-1、阳离子氨基酸转运蛋白（CAT-1）基因表达和精氨酸酶活性。半乳糖凝集素-1 处理导致小胶质细胞极化从 M1 向有益的 M2 表型转变，从而可能预防神经退行性变并促进神经保护。因此，我们的数据表明，半乳糖凝集素-1 通过调节小胶质细胞中的 NO-精氨酸酶网络，可减少中枢神经系统微环境中的神经炎症，从而在 HAND 中发挥神经保护作用。此外，通过将半乳糖凝集素-1 连接到金纳米颗粒（Au-NP）上，可以增强半乳糖凝集素-1 的治疗潜力，从而形成纳米金-半乳糖凝集素-1（Au-Gal-1）多价复合物，通过增加有效载荷流入，比游离半乳糖凝集素-1 具有更高的临床转化功效。
