Department of Medical Neurobiology, Hebrew University-Hadassah Medical School, P.O.B. 12272, Jerusalem 91120, Israel.
FASEB J. 2010 Jul;24(7):2211-21. doi: 10.1096/fj.09-146118. Epub 2010 Feb 23.
A major innate immune function of microglia in the central nervous system is receptor-mediated phagocytosis of tissue debris and pathogens. We studied how phagocytosis of degenerated myelin (i.e., tissue debris) and zymosan (i.e., yeast pathogen) is regulated by the cytoskeleton through myosin light chain kinase (MLCK) and the small GTPase Rho and its effector Rho-kinase (ROCK) in primary mouse microglia. Our observations suggest a dual role of activation and inhibition of phagocytosis by MLCK and Rho/ROCK signaling. MLCK activated, whereas Rho/ROCK down-regulated complement receptor-3 (CR3) mediated, phagocytosis of C3bi-opsonized and nonopsonized myelin. These opposing roles of MLCK and Rho/ROCK depended on the preferential spatial localization of their distinctive functions. MLCK further activated, and Rho/ROCK down-regulated, phagocytosis of nonopsonized zymosan by nonopsonic receptors (e.g., Dectin-1). In contrast, MLCK down-regulated, but Rho/ROCK activated, CR3-mediated phagocytosis of C3bi-opsonized zymosan. Thus MLCK and Rho/ROCK can each activate or inhibit phagocytosis but always act in opposition. Whether activation or inhibition occurs depends on the nature of the phagocytosed particle (C3bi-opsonized or nonopsonized myelin or zymosan) and the receptors mediating each phagocytosis.
小胶质细胞在中枢神经系统中的主要先天免疫功能是通过受体介导吞噬组织碎片和病原体。我们研究了小胶质细胞中的肌球蛋白轻链激酶 (MLCK) 和小 GTP 酶 Rho 及其效应物 Rho-激酶 (ROCK) 通过细胞骨架如何调节对退化髓磷脂 (即组织碎片) 和酵母病原体 (即zymosan) 的吞噬作用。我们的观察结果表明 MLCK 和 Rho/ROCK 信号通路对吞噬作用的激活和抑制具有双重作用。MLCK 激活，而 Rho/ROCK 下调补体受体-3 (CR3) 介导的 C3bi 包被和非包被的髓磷脂吞噬作用。MLCK 和 Rho/ROCK 的这些相反作用取决于其独特功能的优先空间定位。MLCK 进一步激活，而 Rho/ROCK 下调，非调理受体 (如 Dectin-1) 介导的非调理 zymosan 的吞噬作用。相比之下，MLCK 下调，但 Rho/ROCK 激活，CR3 介导的 C3bi 包被的 zymosan 的吞噬作用。因此，MLCK 和 Rho/ROCK 都可以激活或抑制吞噬作用，但总是相互作用。是否发生激活或抑制取决于吞噬颗粒的性质 (C3bi 包被或非包被的髓磷脂或 zymosan) 和介导每种吞噬作用的受体。
