Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158.
Nephrology Unit, Department of Clinical Science, Intervention and Technology, Karolinska Institute, M 99 141 86 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):E11388-E11396. doi: 10.1073/pnas.1808609115. Epub 2018 Nov 9.
Located within the brain's ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis.
脉络丛位于大脑的脑室中，它产生脑脊液，并在中枢神经系统和血液之间形成一个重要的屏障。由于未知的原因，脉络丛会产生高水平的蛋白 klotho。在这里，我们表明这些水平会随着年龄的自然下降。通过靶向病毒载体诱导的 knockout 从脉络丛中选择性耗尽 klotho，会增加多种促炎因子的表达，并触发年轻小鼠中这种结构的巨噬细胞浸润，模拟未经处理的老年小鼠的变化。感染相同 Cre 重组酶表达病毒的野生型小鼠没有表现出这种改变。在体外实验中，当给小鼠注射脂多糖后，从脉络丛中耗尽 klotho 会增强海马体中的小胶质细胞激活。在原代培养物中，klotho 通过增强成纤维细胞生长因子 23 信号来抑制硫氧还蛋白相互作用蛋白依赖性的 NLRP3 炎性小体的激活。我们得出结论，klotho 在脉络丛的大脑和免疫系统界面充当守门员。衰老或疾病时的 klotho 耗竭可能会削弱这种屏障，并促进免疫介导的神经发病机制。
