Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208.
J Immunol. 2020 Jul 15;205(2):502-510. doi: 10.4049/jimmunol.2000037. Epub 2020 Jun 5.
Despite mounting evidence suggesting the involvement of the immune system in regulating brain function, the specific role of immune and inflammatory cells in neurodegenerative diseases remain poorly understood. In this study, we report that depletion of NK cells, a type of innate lymphocytes, alleviates neuroinflammation, stimulates neurogenesis, and improves cognitive function in a triple-transgenic Alzheimer disease (AD) mouse model. NK cells in the brains of triple-transgenic AD mouse model (3xTg-AD) mice exhibited an enhanced proinflammatory profile. Depletion of NK cells by anti-NK1.1 Abs drastically improved cognitive function of 3xTg-AD mice. NK cell depletion did not affect amyloid β concentrations but enhanced neurogenesis and reduced neuroinflammation. Notably, in 3xTg-AD mice depleted of NK cells, microglia demonstrated a homeostatic-like morphology, decreased proliferative response and reduced expression of neurodestructive proinflammatory cytokines. Together, our results suggest a proinflammatory role for NK cells in 3xTg-AD mice and indicate that targeting NK cells might unlock novel strategies to combat AD.
尽管越来越多的证据表明免疫系统在调节大脑功能方面发挥着重要作用，但免疫和炎症细胞在神经退行性疾病中的具体作用仍知之甚少。在这项研究中，我们报告称，自然杀伤 (NK) 细胞的耗竭可减轻神经炎症、刺激神经发生并改善三转基因阿尔茨海默病 (AD) 小鼠模型的认知功能。三转基因 AD 小鼠模型 (3xTg-AD) 大脑中的 NK 细胞表现出增强的促炎特征。用抗 NK1.1 Abs 耗竭 NK 细胞可显著改善 3xTg-AD 小鼠的认知功能。NK 细胞耗竭不影响淀粉样β浓度，但可增强神经发生并减少神经炎症。值得注意的是，在 NK 细胞耗竭的 3xTg-AD 小鼠中，小胶质细胞表现出类似稳态的形态，增殖反应减少，神经破坏性促炎细胞因子的表达降低。总之，我们的结果表明 NK 细胞在 3xTg-AD 小鼠中具有促炎作用，并表明针对 NK 细胞可能为对抗 AD 提供新的策略。
