SHIP-1 Inhibitors improve human microglial-like cell function
SHIP-1 Inhibitors improve human microglial-like cell function
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SHIP-1 抑制剂改善人类小胶质细胞样细胞功能
DOI：
10.4049/jimmunol.206.supp.111.22
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
M. Humphrey
中科院分区：
文献类型：
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作者：
G. S. Ramakrishnan;M. Humphrey
阿尔茨海默病 (AD) 与大脑中 Aβ 斑块的逐渐形成和神经元细胞死亡有关。小胶质细胞维持大脑稳态，其功能障碍与 AD 病理有关。骨髓细胞 #2 (TREM2) 上表达的触发受体可促进小胶质细胞的吞噬作用、迁移和代谢适应性。在巨噬细胞和破骨细胞中，TREM2 信号传导受到包含 INPP5D 编码的肌醇磷酸酶 1 (SHIP-1) 的 src 同源 2 (SH2) 结构域的抑制，并且 rs669 SNP 与大脑 SHIP-1 表达增加相关，并导致 AD 风险。我们假设 SHIP-1 的过度表达会导致 TREM2 信号传导减少以及随后的小胶质细胞功能障碍。为了检验这一假设，我们用 SHIP-1 (SHIPi) (3AC) 及其旁系同源物 SHIP-2 (K161) 的小分子抑制剂处理表达内源性 TREM2、SHIP-1、Iba-1 和 CD68 的人小胶质细胞样 (HMC3) 细胞。通过流式细胞术检测发现，SHIPi 处理显着增加了 TREM2 和 CD68 的表面表达，同时不改变 Iba-1 表达。此外，我们证明用 SHIPi 处理 HMC3 细胞可显着提高其吞噬荧光标记的 Aβ 的能力。在促进吞噬作用的浓度下，SHIPi 在 72 小时内无毒性。总之，这些数据为我们提供了早期证据，表明 SHIPi 可以促进人类小胶质细胞样细胞的吞噬作用。进一步的研究正在进行中，以确定 SHIPi 对代谢健康的影响。 SHIPi 在代谢功能障碍和肥胖的小鼠模型中安全有效，可能是单独或与刺激性 TREM2 抗体联合治疗 AD 的理想治疗方法。
Alzheimer’s disease (AD) is associated with progressive formation of Aβ plaques and neuronal cell death in the brain. Microglia maintain brain homeostasis and their dysfunction is implicated in AD pathology. Triggering receptor expressed on myeloid cells #2 (TREM2) promotes phagocytosis, migration, and metabolic fitness of microglia. TREM2 signaling is inhibited by src-homology 2(SH2) domain containing inositol phosphatase 1 (SHIP-1), encoded by INPP5D, in macrophages and osteoclasts, and the rs669 SNP is associated with increased brain SHIP-1 expression and confers AD risk. We hypothesize that overexpression of SHIP-1 leads to reduced TREM2 signaling and subsequent microglial dysfunction. To test this hypothesis, we treated human microglial like (HMC3) cells, expressing endogenous TREM2, SHIP-1, Iba-1, and CD68, with small molecule inhibitors of SHIP-1 (SHIPi) (3AC) and its paralog SHIP-2 (K161). Treatment with SHIPi significantly increases the surface expression of TREM2 and CD68 as detected by flow cytometry, while not changing Iba-1 expression. Additionally, we demonstrate that treatment of HMC3 cells with SHIPi significantly improves their ability to phagocytose fluorescently tagged Aβ. At concentrations that promote phagocytosis, SHIPi were non-toxic at 72 hours. Together, these data have given us early evidence that SHIPi can promote human microglia-like cell phagocytosis. Further studies are underway to determine the effect of SHIPi on metabolic fitness. SHIPi are safe and effective in mouse models of metabolic dysfunction and obesity and could be an ideal treatment for AD alone or in combination with stimulating TREM2 antibodies.