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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Neuron-microglia interaction induced bi-directional cytotoxicity associated with calpain activation
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Neuron-microglia interaction induced bi-directional cytotoxicity associated with calpain activation

机译：神经元-小胶质细胞相互作用诱导与钙蛋白酶激活相关的双向细胞毒性

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Activated microglia release pro-inflammatory factors and calpain into the extracellular milieu, damaging surrounding neurons. However, mechanistic links to progressive neurodegeneration in disease such as multiple sclerosis (MS) remain obscure. We hypothesize that persistent damaged/dying neurons may also release cytotoxic factors and calpain into the media, which then activate microglia again. Thus, inflammation, neuronal damage, and microglia activation, i. e., bi-directional interaction between neurons and microglia, may be involved in the progressive neurodegeneration. We tested this hypothesis using two in vitro models: (i) the effects of soluble factors from damaged primary cortical neurons upon primary rat neurons and microglia and (ii) soluble factors released from CD3/CD28 activated peripheral blood mononuclear cells of MS patients on primary human neurons and microglia. The first model indicated that neurons due to injury with pro-inflammatory agents (IFN-c) release soluble neurotoxic factors, including COX-2, reactive oxygen species, and calpain, thus activating microglia, which in turn released neurotoxic factors as well. This repeated microglial activation leads to persistent inflammation and neurodegeneration. The released calpain from neurons and microglia was confirmed by the use of calpain inhibitor calpeptin or SNJ-1945 as well as mu- and m-calpain knock down using the small interfering RNA (siRNA) technology. Our second model using activated peripheral blood mononuclear cells, a source of proinflammatory Th1/Th17 cytokines and calpain released from auto-reactive T cells, corroborated similar results in human primary cell cultures and confirmed calpain to be involved in progressive MS. These insights into reciprocal paracrine regulation of cell injury and calpain activation in the progressive phase of MS, Parkinson's disease, and other neurodegenerative diseases suggest potentially beneficial preventive and therapeutic strategies, including calpain inhibition.
机译：活化的小胶质细胞将促炎因子和钙蛋白酶释放到细胞外环境中，从而破坏周围的神经元。但是，与疾病（例如多发性硬化症（MS））中进行性神经退行性改变的机制联系仍然不清楚。我们假设持续的受损/垂死神经元也可能释放细胞毒性因子和钙蛋白酶进入培养基，然后再次激活小胶质细胞。因此，发炎，神经元损伤和小胶质细胞活化。例如，神经元和小胶质细胞之间的双向相互作用可能与进行性神经变性有关。我们使用两个体外模型测试了这一假设：（i）受损的原皮神经元的可溶性因子对原代大鼠神经元和小胶质细胞的影响，以及（ii）MS患者CD3 / CD28活化的外周血单核细胞释放的可溶性因子人类神经元和小胶质细胞。第一个模型表明，由于促炎剂（IFN-c）损伤而引起的神经元释放了可溶性神经毒性因子，包括COX-2，活性氧和钙蛋白酶，从而激活了小胶质细胞，进而释放了神经毒性因子。这种反复的小胶质细胞活化导致持续的炎症和神经变性。通过使用钙蛋白酶抑制剂calpeptin或SNJ-1945以及使用小干扰RNA（siRNA）技术的mu-和m-calpain抑制作用，证实了神经元和小胶质细胞释放的钙蛋白酶。我们的第二个模型使用活化的外周血单核细胞，促炎性Th1 / Th17细胞因子和自反应性T细胞释放的钙蛋白酶的来源，证实了人类原代细胞培养物中的相似结果，并证实了钙蛋白酶参与了进行性MS。这些对MS，帕金森氏病和其他神经退行性疾病进展期细胞损伤和钙蛋白酶激活的相互旁分泌调节的见解表明了潜在的有益预防和治疗策略，包括抑制钙蛋白酶。

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