Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
FASEB J. 2023 Nov;37(11):e23242. doi: 10.1096/fj.202300462RR.
TIAM Rac1-associated GEF 2 short form (TIAM2S) as an oncoprotein alters the immunity of peripheral immune cells to construct an inflammatory tumor microenvironment. However, its role in the activation of microglia, the primary innate immune cells of the brain, and neuroinflammation remains unknown. This study investigated the mechanism underlying TIAM2S shapes immune properties of microglia to facilitate neuron damage. Human microglial clone 3 cell line (HMC3) and human brain samples were applied to determine the presence of TIAM2S in microglia by western blots and double immunostaining. Furthermore, TIAM2S transgenic mice combined with multiple reconstituted primary neuron-glial culture systems and a cytokine array were performed to explore how TIAM2S shaped immune priming of microglia and participated in lipopolysaccharide (LPS)-induced neuron damage. TIAM2S protein was detectable in HMC3 cells and presented in a small portion (~11.1%) of microglia in human brains referred to as TIAM2S-positive microglia. With the property of secreted soluble factor-mediated immune priming, TIAM2S-positive microglia enhanced LPS-induced neuroinflammation and neural damage in vivo and in vitro. The gain- and loss-of-function experiments showed soluble intercellular adhesion molecule-1 (sICAM-1) participated in neurotoxic immune priming of TIAM2S+ microglia. Together, this study demonstrated a novel TIAM2S-positive microglia subpopulation enhances inflammation and neurotoxicity through sICAM-1-mediated immune priming.
TIAM Rac1 相关鸟苷酸交换因子 2 短型（TIAM2S）作为一种癌蛋白，改变外周免疫细胞的免疫功能，构建炎症性肿瘤微环境。然而，其在大脑主要固有免疫细胞——小胶质细胞的激活以及神经炎症中的作用尚不清楚。本研究旨在探讨 TIAM2S 改变小胶质细胞免疫特性从而促进神经元损伤的机制。通过 Western blot 和双重免疫染色，应用人小胶质细胞克隆 3 细胞系（HMC3）和人脑样本，确定 TIAM2S 在小胶质细胞中的存在。此外，通过 TIAM2S 转基因小鼠与多种重建原代神经元-神经胶质培养系统和细胞因子阵列联合实验，探讨 TIAM2S 如何塑造小胶质细胞的免疫启动，并参与脂多糖（LPS）诱导的神经元损伤。TIAM2S 蛋白可在 HMC3 细胞中检测到，并存在于一小部分 (~11.1%)人脑小胶质细胞中，被称为 TIAM2S 阳性小胶质细胞。具有分泌可溶性因子介导的免疫启动特性，TIAM2S 阳性小胶质细胞增强了 LPS 诱导的体内和体外神经炎症和神经损伤。获得和丧失功能实验表明，细胞间黏附分子-1（sICAM-1）参与了 TIAM2S+小胶质细胞的神经毒性免疫启动。综上所述，本研究表明一种新型的 TIAM2S 阳性小胶质细胞亚群通过 sICAM-1 介导的免疫启动增强炎症和神经毒性。
