IL-1β impairs retrograde flow of BDNF signaling by attenuating endosome trafficking.
IL-1β impairs retrograde flow of BDNF signaling by attenuating endosome trafficking.
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DOI：
10.1186/s12974-017-0803-z
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发表时间：
2017-02-02
影响因子：
9.3
通讯作者：
Cotman CW
中科院分区：
文献类型：
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作者：
Carlos AJ;Tong L;Prieto GA;Cotman CW
随着年龄的增长和阿尔茨海默病，促炎细胞因子在大脑中积累，并可能损害神经元的健康和认知功能。脑源性神经营养因子（BDNF）是支持神经元健康、功能和突触可塑性的关键神经营养因子。促炎细胞因子白介素-1β (IL-1β)损害BDNF信号传导，但是否影响BDNF信号传导内体运输尚未研究。本研究采用体外方法在原代海马神经元中评估IL-1β对BDNF信号核内体运输的影响。神经元在分离细胞体及其轴突末端环境的微流体室中培养，使我们能够在轴突室中特异性治疗并实时追踪囊泡运输。我们发现IL-1β在整个培养网络中减弱BDNF信号内体。在il -1β处理的细胞中，总体BDNF内体密度降低，BDNF内体与突触前终末的共定位发现比对照培养高出两倍以上。选择性IL-1β治疗微流控室突触前腔室减弱BDNF内体通量，通过减少小体腔室中BDNF- gfp内体计数来测量。此外，IL-1β降低了BDNF诱导的Erk5磷酸化，Erk5是已知的BDNF逆行转运靶点。从机制上讲，运输缺陷不是由于BDNF- trkb复合物的内吞作用受损或运输速率受损，因为在对照组和IL-1β治疗组中，BDNF内体的运输速率相同。突触前核内体分选的调节因子包括翻译后修饰，泛素化。为了支持这种可能性，il -1β介导的bdnf诱导的Erk5磷酸化抑制可以通过外源性泛素c端水解酶L1 （UCH-L1）来挽救，这是一种调节泛素和内体运输的去泛素化酶。我们观察到一种神经营养抵抗状态，即在IL-1β长期存在的情况下，BDNF不能通过信号内体的逆行运输有效地传递长距离信号。由于IL-1β积累是许多神经退行性疾病的不变特征，我们的研究表明，受损的BDNF逆行转运依赖信号可能在神经退行性疾病中具有重要意义。
Pro-inflammatory cytokines accumulate in the brain with age and Alzheimer’s disease and can impair neuron health and cognitive function. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin that supports neuron health, function, and synaptic plasticity. The pro-inflammatory cytokine interleukin-1β (IL-1β) impairs BDNF signaling but whether it affects BDNF signaling endosome trafficking has not been studied. This study uses an in vitro approach in primary hippocampal neurons to evaluate the effect of IL-1β on BDNF signaling endosome trafficking. Neurons were cultured in microfluidic chambers that separate the environments of the cell body and its axon terminal, enabling us to specifically treat in axon compartments and trace vesicle trafficking in real-time. We found that IL-1β attenuates BDNF signaling endosomes throughout networks in cultures. In IL-1β-treated cells, overall BDNF endosomal density was decreased, and the colocalization of BDNF endosomes with presynaptic terminals was found to be more than two times higher than in control cultures. Selective IL-1β treatment to the presynaptic compartment in microfluidic chamber attenuated BDNF endosome flux, as measured by reduced BDNF-GFP endosome counts in the somal compartment. Further, IL-1β decreased the BDNF-induced phosphorylation of Erk5, a known BDNF retrograde trafficking target. Mechanistically, the deficiency in trafficking was not due to impaired endocytosis of the BDNF-TrkB complex, or impaired transport rate, since BDNF endosomes traveled at the same rate in both control and IL-1β treatment groups. Among the regulators of presynaptic endosome sorting is the post-translational modification, ubiquitination. In support of this possibility, the IL-1β-mediated suppression of BDNF-induced Erk5 phosphorylation can be rescued by exogenous ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that regulates ubiquitin and endosomal trafficking. We observed a state of neurotrophic resistance whereby, in the prolonged presence of IL-1β, BDNF is not effective in delivering long-distance signaling via the retrograde transport of signaling endosomes. Since IL-1β accumulation is an invariant feature across many neurodegenerative diseases, our study suggest that compromised BDNF retrograde transport-dependent signaling may have important implications in neurodegenerative diseases.