背景:作为分泌的信号蛋白的骨桥蛋白(OPN)在响应细胞损伤和神经变性时被显著诱导。大脑中的小胶质细胞炎症反应与神经退行性疾病的神经病理学标志密切相关。但是对分子机制的理解在一些情况下仍然知之甚少。
方法:使用放射性配体检测大脑中易位蛋白(TSPO)受体表达增加的微正电子发射断层扫描(PET)神经成像是一种非侵入性工具,用于追踪活体哺乳动物的神经炎症。
结果:在人源化中,慢性HIV感染的雌性小鼠,其中OPN表达被功能性适体敲低,TSPO放射性配体DPA-713的摄取在皮质中明显上调,嗅觉灯泡,基底前脑,下丘脑,与对照组相比,中央灰质。对Iba-1免疫反应的小胶质细胞在一些感染HIV的小鼠中更丰富,但总的来说,组间差异不显著.TSPO+小胶质细胞很容易通过死后脑组织的免疫标记检测到,两种类型的神经元也对TSPO选择性染色为阳性。反应细胞是小脑的特殊神经元,浦肯野细胞,和黑质的酪氨酸羟化酶阳性神经元的子集。
结论:在具有野生型骨桥蛋白水平的雌性小鼠中,在HIV持续复制水平最高的动物中观察到大脑中TSPO配体摄取水平增加。相比之下,在骨桥蛋白水平较低的小鼠中,观察到最高水平的TSPO摄取,在持续感染水平相对较低的小鼠中。这些发现表明,骨桥蛋白可能在大脑中起分子制动调节作用,对HIV感染的炎症反应。
BACKGROUND: Osteopontin (OPN) as a secreted signaling protein is dramatically induced in response to cellular injury and neurodegeneration. Microglial inflammatory responses in the brain are tightly associated with the neuropathologic hallmarks of neurodegenerative disease, but understanding of the molecular mechanisms remains in several contexts poorly understood.
METHODS: Micro-positron emission tomography (PET) neuroimaging using radioligands to detect increased expression of the translocator protein (TSPO) receptor in the brain is a non-invasive tool used to track neuroinflammation in living mammals.
RESULTS: In humanized, chronically HIV-infected female mice in which OPN expression was knocked down with functional aptamers, uptake of TSPO radioligand DPA-713 was markedly upregulated in the cortex, olfactory bulb, basal forebrain, hypothalamus, and central grey matter compared to controls. Microglia immunoreactive for Iba-1 were more abundant in some HIV-infected mice, but overall, the differences were not significant between groups. TSPO+ microglia were readily detected by immunolabeling of post-mortem brain tissue and unexpectedly, two types of neurons also selectively stained positive for TSPO. The reactive cells were the specialized neurons of the cerebellum, Purkinje cells, and a subset of tyrosine hydroxylase-positive neurons of the substantia nigra.
CONCLUSIONS: In female mice with wild-type levels of osteopontin, increased levels of TSPO ligand uptake in the brain was seen in animals with the highest levels of persistent HIV replication. In contrast, in mice with lower levels of osteopontin, the highest levels of TSPO uptake was seen, in mice with relatively low levels of persistent infection. These findings suggest that osteopontin may act as a molecular brake regulating in the brain, the inflammatory response to HIV infection.