Falk Irene, Maric Dragan, Leibovitch Emily, Sati Pascal, Lefeuvre Jennifer, Luciano Nicholas J, Guy Joseph, Ha Seung-Kwon, Owen David R, Aigbirhio Franklin, Matthews Paul M, Reich Daniel S, Jacobson Steven
Viral Immunology Section, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Building 10, Room 5C103, 10 Center Drive, Bethesda, MD, 20892-1400, USA.
Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK.
J Neuroinflammation. 2025 Jan 27;22(1):19. doi: 10.1186/s12974-025-03343-4.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and is a leading non-traumatic cause of disability in young adults. The 18 kDa Translocator Protein (TSPO) is a mitochondrial protein and positron emission tomography (PET)-imaging target that is highly expressed in MS brain lesions. It is used as an inflammatory biomarker and has been proposed as a therapeutic target. However, its specific pathological significance in humans is not well understood. Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a well-established primate model of MS. Studying TSPO expression in this model will enhance our understanding of its expression in MS. This study therefore characterizes patterns of TSPO expression in fixed CNS tissues from one non-EAE control marmoset and 8 EAE marmosets using multiplex immunofluorescence. In control CNS tissue, we find that TSPO is expressed in the leptomeninges, ependyma, and over two-thirds of Iba1 + microglia, but not astrocytes or neurons. In Iba1 + cells in both control and acute EAE tissue, we find that TSPO is co-expressed with markers of antigen presentation (CD74), early activation (MRP14), phagocytosis (CD163) and anti-inflammatory phenotype (Arg1); a high level of TSPO expression is not restricted to a particular microglial phenotype. While TSPO is expressed in over 88% of activated Iba1 + cells in acute lesions in marmoset EAE, it also is sometimes observed in subsets of astrocytes and neurons. Additionally, we find the percentage of Iba1 + cells expressing TSPO declines significantly in lesions > 5 months old and may be as low as 13% in chronic lesions. However, we also find increased astrocytic TSPO expression in chronic-appearing lesions with astrogliosis. Finally, we find expression of TSPO in a subset of neurons, most frequently GLS2 + glutamatergic neurons. The shift in TSPO expression from Iba + microglia/macrophages to astrocytes over time is similar to patterns suggested by earlier neuropathology studies in MS. Thus, marmoset EAE appears to be a clinically relevant model for the study of TSPO in immune dysregulation in human disease.
多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症性脱髓鞘疾病，是年轻成年人非创伤性致残的主要原因。18 kDa转位蛋白（TSPO）是一种线粒体蛋白，也是正电子发射断层扫描（PET）成像靶点，在MS脑损伤中高度表达。它被用作炎症生物标志物，并已被提议作为治疗靶点。然而，其在人类中的具体病理意义尚不完全清楚。普通狨猴的实验性自身免疫性脑脊髓炎（EAE）是一种成熟的MS灵长类动物模型。研究该模型中TSPO的表达将增进我们对其在MS中表达的理解。因此，本研究使用多重免疫荧光对1只非EAE对照狨猴和8只EAE狨猴的固定CNS组织中TSPO的表达模式进行了表征。在对照CNS组织中，我们发现TSPO在软脑膜、室管膜以及超过三分之二的Iba1+小胶质细胞中表达，但在星形胶质细胞或神经元中不表达。在对照和急性EAE组织的Iba1+细胞中，我们发现TSPO与抗原呈递标志物（CD74）、早期激活标志物（MRP14）、吞噬作用标志物（CD163）和抗炎表型标志物（Arg1）共表达；高水平的TSPO表达并不局限于特定的小胶质细胞表型。虽然TSPO在狨猴EAE急性损伤中超过88%的活化Iba1+细胞中表达，但有时也在星形胶质细胞和神经元亚群中观察到。此外，我们发现，在大于5个月的损伤中，表达TSPO的Iba1+细胞百分比显著下降，在慢性损伤中可能低至13%。然而，我们还发现在出现星形胶质细胞增生的慢性损伤中，星形胶质细胞TSPO表达增加。最后，我们发现在一部分神经元中，最常见的是GLS2+谷氨酸能神经元中存在TSPO表达。随着时间的推移，TSPO表达从Iba+小胶质细胞/巨噬细胞向星形胶质细胞的转变与MS早期神经病理学研究提出的模式相似。因此，狨猴EAE似乎是研究人类疾病免疫失调中TSPO的一个临床相关模型。
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