Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia.
Department of Neurobiology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia.
J Alzheimers Dis. 2018;61(2):619-630. doi: 10.3233/JAD-170538.
Alzheimer's disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer's patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-γ, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-β, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorγt, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology.
阿尔茨海默病（AD）的特征是淀粉样β斑块的积累，这进一步促进了小胶质细胞介导的神经炎症反应和大脑中的炎症。新出现的数据揭示了肠道相关淋巴组织（GALT）细胞与中枢神经系统之间的关系，因为在肠道中被激活的效应细胞可能会归巢到大脑。本研究旨在确定 5xFAD 小鼠（AD 的一种既定模型）的 GALT 细胞组成。用表面和细胞内标记物对从小肠集合淋巴结（PP）和肠系膜淋巴结（MLN）分离的免疫细胞进行染色，用于 T 辅助（Th）亚群、B 淋巴细胞和巨噬细胞，并进行流式细胞术分析，同时通过 qPCR 和 ELISA 分别确定细胞因子表达和产生。在具有既定 AD 病理学的 5xFAD 小鼠的 GALT 中检测到炎症。尽管两种品系的 IFN-γ、IL-4 和 IL-10 产生相当，但在 PP 和 MLN 细胞中观察到 IL-17 的产生较低。这种现象不能归因于 Th17 细胞的丰度较低，或起始其形成或增殖的细胞因子（TGF-β、IL-6 和 IL-23）。此外，IL-17 产生减少不是 Il-17 mRNA 转录改变或关键转录因子 Rorγt 缺乏的结果。然而，miR-155（一种促进 Th17 细胞发育的非编码 micro RNA）的表达在 5xFAD 小鼠的 MLN 细胞中显著降低。相比之下，没有 AD 神经病理学的小鼠的 GALT 没有炎症或 Th17 数量改变，也没有减少 IL-17 的产生。总之，5xFAD 小鼠 GALT 中的观察到的变化反映了疾病进展，可能反映了肠道中免疫监视不足，并导致 AD 病理学增强。
