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首页> 外文期刊>Journal of neuroinflammation >Primary phagocytosis of viable neurons by microglia activated with LPS or Aβ is dependent on calreticulin/LRP phagocytic signalling
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Primary phagocytosis of viable neurons by microglia activated with LPS or Aβ is dependent on calreticulin/LRP phagocytic signalling

机译：LPS或Aβ激活的小胶质细胞对存活神经元的初级吞噬作用取决于钙网蛋白/ LRP吞噬信号

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Background Microglia are resident brain macrophages that can phagocytose dead, dying or viable neurons, which may be beneficial or detrimental in inflammatory, ischaemic and neurodegenerative brain pathologies. Cell death caused by phagocytosis of an otherwise viable cell is called ‘primary phagocytosis’ or ‘phagoptosis’. Calreticulin (CRT) exposure on the surface of cancer cells can promote their phagocytosis via LRP (low-density lipoprotein receptor-related protein) on macrophages, but it is not known whether this occurs with neurons and microglia. Methods We used primary cultures of cerebellar neurons, astrocytes and microglia to investigate the potential role of CRT/LRP phagocytic signalling in the phagocytosis of viable neurons by microglia stimulated with lipopolysaccharide (LPS) or nanomolar concentrations of amyloid-β peptide1-42 (Aβ). Exposure of CRT on the neuronal surface was investigated using surface biotinylation and western blotting. A phagocytosis assay was also developed using BV2 and PC12 cell lines to investigate CRT/LRP signalling in microglial phagocytosis of apoptotic cells. Results We found that BV2 microglia readily phagocytosed apoptotic PC12 cells, but this was inhibited by a CRT-blocking antibody or LRP-blocking protein (receptor-associated protein: RAP). Activation of primary rat microglia with LPS or Aβ resulted in loss of co-cultured cerebellar granule neurons, and this was blocked by RAP or antibodies against CRT or against LRP, preventing all neuronal loss and death. CRT was present on the surface of viable neurons, and this exposure did not change in inflammatory conditions. CRT antibodies prevented microglia-induced neuronal loss when added to neurons, while LRP antibodies prevented neuronal loss when added to the microglia. Pre-binding of CRT to neurons promoted neuronal loss if activated microglia were added, but pre-binding of CRT to microglia or both cell types prevented microglia-induced neuronal loss. Conclusions CRT exposure on the surface of viable or apoptotic neurons appears to be required for their phagocytosis via LRP receptors on activated microglia, but free CRT can block microglial phagocytosis of neurons by acting on microglia. Phagocytosis of CRT-exposing neurons by microglia can be a direct cause of neuronal death during inflammation, and might therefore contribute to neurodegeneration and be prevented by blocking the CRT/LRP pathway.
机译：背景小胶质细胞是常驻的大脑巨噬细胞，可吞噬死亡，垂死或存活的神经元，在炎症，局部缺血和神经退行性脑病中可能是有益的或有害的。由吞噬作用原本可以存活的细胞引起的细胞死亡称为“原发吞噬作用”或“吞噬作用”。钙网蛋白（CRT）暴露于癌细胞表面可通过巨噬细胞上的LRP（低密度脂蛋白受体相关蛋白）促进其吞噬作用，但尚不清楚这是否发生在神经元和小胶质细胞上。方法我们使用小脑神经元，星形胶质细胞和小胶质细胞的原代培养物来研究CRT / LRP吞噬信号在脂多糖（LPS）或纳摩尔浓度的淀粉样β-肽1-42（Aβ）刺激的小胶质细胞吞噬活细胞中的潜在作用。 。使用表面生物素化和蛋白质印迹研究了CRT在神经元表面的暴露。还使用BV2和PC12细胞系开发了吞噬作用测定法，以研究凋亡小细胞吞噬作用中的CRT / LRP信号传导。结果我们发现BV2小胶质细胞容易吞噬凋亡的PC12细胞，但是被CRT阻断抗体或LRP阻断蛋白（受体相关蛋白：RAP）抑制。用LPS或Aβ激活原代大鼠小神经胶质细胞会导致共培养的小脑颗粒神经元丢失，这被RAP或抗CRT或LRP抗体阻断，从而防止了所有神经元丢失和死亡。 CRT存在于存活的神经元表面，并且这种接触在炎症条件下没有改变。当添加到神经元中时，CRT抗体阻止了小胶质细胞诱导的神经元丢失，而当添加到小神经胶质时，LRP抗体阻止了神经胶质丢失。如果添加活化的小胶质细胞，CRT与神经元的预结合会促进神经元的损失，但是CRT与小胶质细胞或这两种细胞类型的预结合可防止小胶质细胞诱导的神经元的损失。结论活的或凋亡的神经元表面上的CRT暴露似乎是通过活化的小胶质细胞上的LRP受体进行吞噬作用所必需的，但是游离的CRT可以通过作用于小胶质细胞来阻止神经元的小胶质细胞吞噬作用。小胶质细胞对暴露于CRT的神经元的吞噬作用可能是炎症期间神经元死亡的直接原因，因此可能导致神经退行性变，可以通过阻止CRT / LRP途径来预防。

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