Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.
Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.
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DOI：
10.1371/journal.pbio.1002466
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发表时间：
2016-05
期刊：
影响因子：
9.8
通讯作者：
Sierra A
中科院分区：
文献类型：
--
作者：
Abiega O;Beccari S;Diaz-Aparicio I;Nadjar A;Layé S;Leyrolle Q;Gómez-Nicola D;Domercq M;Pérez-Samartín A;Sánchez-Zafra V;Paris I;Valero J;Savage JC;Hui CW;Tremblay MÈ;Deudero JJ;Brewster AL;Anderson AE;Zaldumbide L;Galbarriatu L;Marinas A;Vivanco Md;Matute C;Maletic-Savatic M;Encinas JM;Sierra A
吞噬作用对于维持大量炎性和自身免疫性疾病中的组织稳态是必不可少的，但其在患病脑中的作用却很少被探索。最近的研究结果表明，在成年海马神经原性龛，其中过量的新生细胞在生理条件下进行凋亡，吞噬作用有效地执行监视，分枝小胶质细胞。为了测试小胶质细胞是否也是患病大脑中的有效吞噬细胞，我们让它们面对一系列凋亡挑战，并发现了一种普遍的反应。当受到体外兴奋性毒性（通过谷氨酸激动剂NMDA）或体内炎症（通过细菌脂多糖的全身给药或通过ω 3脂肪酸缺乏饮食）的挑战时，小胶质细胞采取不同的策略来提高其吞噬效率并补偿凋亡细胞数量的增加，从而保持吞噬作用和凋亡紧密耦合。出乎意料的是，这种耦合在内侧颞叶癫痫（MTLE）的小鼠模型以及从患有MTLE的个体切除的海马组织中长期丢失，MTLE是一种主要的神经系统疾病，其特征在于癫痫发作、兴奋性毒性和炎症。重要的是，吞噬/凋亡偶联的丧失与小胶质细胞促炎性、致癫痫细胞因子的表达相关，表明其对癫痫病理生理学的贡献。吞噬细胞的封锁导致减少小胶质细胞的监视和凋亡细胞识别受体的表达，并不直接介导的信号通过小胶质细胞谷氨酸受体。相反，它与海马网络过度活跃引起的局部ATP微梯度破坏有关，至少在癫痫急性期是这样。最后，解偶联导致凋亡新生细胞在神经原性小生境中的积累，这不是由于存活率降低，而是由于癫痫发作后细胞清除延迟。这些结果表明，小胶质细胞吞噬的效率严重影响细胞凋亡的动力学，并敦促常规评估神经退行性疾病中的小胶质细胞吞噬效率。小胶质细胞的吞噬作用与细胞凋亡密切相关，迅速清除凋亡细胞并积极维持组织稳态，但与癫痫相关的神经元过度活跃破坏了驱动吞噬作用的ATP梯度，导致凋亡细胞和炎症的积累。吞噬作用，吞噬和消化细胞碎片，是受损组织再生反应的核心，因为它防止有毒细胞内内容物的溢出，并积极抗炎。在大脑中，专职吞噬细胞是小胶质细胞，其动态过程迅速吞噬和降解在生理条件下经历凋亡-程序性细胞死亡的细胞。因此，小胶质细胞是大脑再生的关键，但它们在患病大脑中作为吞噬细胞的效率只是推测。在这里，我们发现了小胶质细胞对兴奋性毒性和炎症诱导的凋亡挑战的一般性反应，其中它们提高了吞噬效率以解释凋亡的增加。令我们惊讶的是，这种凋亡/小胶质细胞吞噬偶联在人类和实验性内侧颞叶癫痫（MTLE）的海马中丢失，MTLE是一种以兴奋性毒性、炎症和癫痫发作为特征的主要神经退行性疾病。这种解偶联是由于在神经元过度活跃期间广泛的ATP释放，其使小胶质细胞对由凋亡细胞释放的ATP微梯度作为“发现我”信号”失明“。吞噬功能的损害导致凋亡细胞的积累和有害的炎症反应的积累。我们的数据主张系统评估小胶质细胞吞噬作用在脑疾病中的效率。
Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders. Phagocytosis by microglia is tightly coupled to apoptosis, swiftly removing apoptotic cells and actively maintaining tissue homeostasis, but the neuronal hyperactivity associated with epilepsy disrupts the ATP gradients that drive phagocytosis, leading to the accumulation of apoptotic cells and inflammation. Phagocytosis, the engulfment and digestion of cellular debris, is at the core of the regenerative response of the damaged tissue, because it prevents the spillover of toxic intracellular contents and is actively anti-inflammatory. In the brain, the professional phagocytes are microglia, whose dynamic processes rapidly engulf and degrade cells undergoing apoptosis—programmed cell death—in physiological conditions. Thus, microglia hold the key to brain regeneration, but their efficiency as phagocytes in the diseased brain is only presumed. Here, we have discovered a generalized response of microglia to apoptotic challenge induced by excitotoxicity and inflammation, in which they boost their phagocytic efficiency to account for the increase in apoptosis. To our surprise, this apoptosis/microglial phagocytosis coupling was lost in the hippocampus from human and experimental mesial temporal lobe epilepsy (MTLE), a major neurodegenerative disorder characterized by excitotoxicity, inflammation, and seizures. This uncoupling was due to widespread ATP release during neuronal hyperactivity, which “blinded” microglia to the ATP microgradients released by apoptotic cells as “find-me” signals. The impairment of phagocytosis led to the accumulation of apoptotic cells and the build-up of a detrimental inflammatory reaction. Our data advocates for systematic assessment of the efficiency of microglial phagocytosis in brain disorders.