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酪氨酸激酶受体调节小胶质细胞生理学的多个特征。

TAM receptors regulate multiple features of microglial physiology.

作者信息

Fourgeaud Lawrence, Través Paqui G, Tufail Yusuf, Leal-Bailey Humberto, Lew Erin D, Burrola Patrick G, Callaway Perri, Zagórska Anna, Rothlin Carla V, Nimmerjahn Axel, Lemke Greg

机构信息

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA USA 92037.

Waitt Advanced Biophotonics Center, The Salk Institute for Biological Studies, La Jolla, CA USA 92037.

出版信息

Nature. 2016 Apr 14;532(7598):240-244. doi: 10.1038/nature17630. Epub 2016 Apr 6.

DOI:10.1038/nature17630
PMID:27049947
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5358512/
Abstract

Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson's disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.

摘要

小胶质细胞是中枢神经系统（CNS）的损伤传感器，也是负责对死亡脑细胞进行常规非炎症性清除的吞噬细胞。在此我们表明，TAM受体酪氨酸激酶Mer和Axl调节这些小胶质细胞功能。我们发现，成年小鼠若小胶质细胞中缺乏Mer和Axl，会在CNS的神经发生区域特异性地出现凋亡细胞的明显积累，并且成年神经发生过程中产生的凋亡细胞的小胶质细胞吞噬作用通常由TAM受体配体Gas6和蛋白S驱动。利用实时双光子成像，我们证明小胶质细胞对脑损伤的反应也受TAM调节，因为缺乏TAM的小胶质细胞表现出突起运动性降低以及向损伤部位聚集延迟。最后，我们表明在帕金森病小鼠模型中形成的炎症环境中，小胶质细胞Axl的表达显著上调。总之，这些结果确立了TAM受体既是小胶质细胞生理学的调控因子，也是CNS疾病治疗干预的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6532/5358512/790055d726b1/nihms-765141-f0004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6532/5358512/358b9c0ab086/nihms-765141-f0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6532/5358512/37dd024aef96/nihms-765141-f0011.jpg
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