LRRC8A is dispensable for a variety of microglial functions and response to acute stroke.
LRRC8A is dispensable for a variety of microglial functions and response to acute stroke.
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小胶质细胞，常驻脑免疫细胞，在协调对中枢神经系统（CNS）损伤的反应中至关重要。许多小胶质细胞功能，如吞噬作用，运动性和趋化性，被认为依赖于氯离子通道，包括体积调节阴离子通道（VRAC），但迄今为止的研究依赖于使用特异性有限的药理学工具。VRAC也被提议作为急性CNS损伤的药物靶标，其在小胶质细胞功能中的作用对于开发CNS治疗剂具有相当大的兴趣。本研究旨在通过使用条件性LRRC8A基因敲除小鼠（其在小胶质细胞中缺乏必需的VRAC亚基LRRC8A）来明确证实VRAC在小胶质细胞功能中的贡献。我们证明，虽然VRAC有助于细胞体积调节，但它对吞噬活性，细胞迁移或P2YR12依赖性趋化性没有影响。此外，小胶质细胞VRAC的损失并不影响小胶质细胞形态或中风后缺血性损伤的程度。我们的结论是，VRAC并不严格调节小胶质细胞对脑损伤的反应，并且可以靶向其他CNS细胞类型（例如，星形胶质细胞）而不妨碍小胶质细胞功能。我们的研究结果还表明VRAC在细胞体积调节中的作用，但表明VRAC不参与以前认为调节的几种主要细胞功能，并指出先天免疫中氯离子转运的其他替代机制。LRRC8A KO不影响小胶质细胞吞噬或迁移。LRRC8A不调节小胶质细胞P2RY12依赖的趋化性或形态。小胶质细胞LRRC8A不影响缺血性卒中损伤。
Microglia, resident brain immune cells, are critical in orchestrating responses to central nervous system (CNS) injury. Many microglial functions, such as phagocytosis, motility and chemotaxis, are suggested to rely on chloride channels, including the volume‐regulated anion channel (VRAC), but studies to date have relied on the use of pharmacological tools with limited specificity. VRAC has also been proposed as a drug target for acute CNS injury, and its role in microglial function is of considerable interest for developing CNS therapeutics. This study aimed to definitively confirm the contribution of VRAC in microglia function by using conditional LRRC8A‐knockout mice, which lacked the essential VRAC subunit LRRC8A in microglia. We demonstrated that while VRAC contributed to cell volume regulation, it had no effect on phagocytic activity, cell migration or P2YR12‐dependent chemotaxis. Moreover, loss of microglial VRAC did not affect microglial morphology or the extent of ischemic damage following stroke. We conclude that VRAC does not critically regulate microglial responses to brain injury and could be targetable in other CNS cell types (e.g., astrocytes) without impeding microglial function. Our results also demonstrate a role for VRAC in cell volume regulation but show that VRAC is not involved in several major cellular functions that it was previously thought to regulate, and point to other, alternative mechanisms of chloride transport in innate immunity. LRRC8A KO does not affect microglial phagocytosis or migration. LRRC8A does not regulate microglial P2RY12‐dependent chemotaxis or morphology. Microglial LRRC8A does not affect ischaemic stroke damage.
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影响因子：
6.2
作者：
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