Phagocytic receptors activate and immune inhibitory receptor SIRPα inhibits phagocytosis through paxillin and cofilin.
Phagocytic receptors activate and immune inhibitory receptor SIRPα inhibits phagocytosis through paxillin and cofilin.
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DOI：
10.3389/fncel.2014.00104
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发表时间：
2014
影响因子：
5.3
通讯作者：
Rotshenker S
中科院分区：
文献类型：
--
作者：
Gitik M;Kleinhaus R;Hadas S;Reichert F;Rotshenker S
吞噬凋亡细胞、组织碎片、病原体和癌细胞的先天免疫功能对于动态平衡、组织修复、抗感染和抗癌是必不可少的。吞噬作用在中枢神经系统(CNS)中由驻留的小胶质细胞执行，在CNS和周围神经系统中由招募的巨噬细胞执行。当吞噬作用继续进行时，旁观者健康细胞通过向吞噬细胞发送“不要吃我”的信息来保护自己，因为它们表面的CD47与吞噬细胞表面的免疫抑制受体Sirpα连接，然后Sirpα产生抑制吞噬的信号。当组织碎片和不健康的细胞通过同样的机制抑制自己的吞噬功能时，这种有益的机制变得有害。然而，Sirpα产生的抑制信号还没有完全被揭示。在这里，我们集中讨论Sirpα是如何抑制组织碎片“变性髓鞘”的吞噬作用的，这种吞噬作用阻碍了轴突损伤和神经退行性疾病的修复。我们测试了sirpα是否通过Paxlin和Cofilin调节细胞骨架功能来抑制吞噬作用，因为(A)细胞骨架产生驱动吞噬的机械力，以及(B)Paxlin和Cofilin共同控制细胞骨架功能。当吞噬作用被激活时，小胶质细胞中的帕西林和柯菲林被瞬时激活。相反，当Sirpα-shRNA下调小胶质细胞中Sirpα的表达时，Paxlin和Cofilin被持续激活，吞噬功能增强。此外，吞噬水平、巴西林激活水平和粘附素激活水平彼此之间呈正相关。综上所述，这些观察结果提示了一种新的机制，即通过促进巴西林和柯菲林激活吞噬细胞受体产生的激活信号和通过促进巴西林和柯菲林失活而产生的免疫抑制Sirpα产生的抑制信号来控制吞噬作用。
The innate immune function of phagocytosis of apoptotic cells, tissue debris, pathogens, and cancer cells is essential for homeostasis, tissue repair, fighting infection, and combating malignancy. Phagocytosis is carried out in the central nervous system (CNS) by resident microglia and in both CNS and peripheral nervous system by recruited macrophages. While phagocytosis proceeds, bystander healthy cells protect themselves by sending a “do not eat me” message to phagocytes as CD47 on their surface ligates immune inhibitory receptor SIRPα on the surface of phagocytes and SIRPα then produces the signaling which inhibits phagocytosis. This helpful mechanism becomes harmful when tissue debris and unhealthy cells inhibit their own phagocytosis by employing the same mechanism. However, the inhibitory signaling that SIRPα produces has not been fully revealed. We focus here on how SIRPα inhibits the phagocytosis of the tissue debris “degenerated myelin” which hinders repair in axonal injury and neurodegenerative diseases. We tested whether SIRPα inhibits phagocytosis by regulating cytoskeleton function through paxillin and cofilin since (a) the cytoskeleton generates the mechanical forces that drive phagocytosis and (b) both paxillin and cofilin control cytoskeleton function. Paxillin and cofilin were transiently activated in microglia as phagocytosis was activated. In contrast, paxillin and cofilin were continuously activated and phagocytosis augmented in microglia in which SIRPα expression was knocked-down by SIRPα-shRNA. Further, levels of phagocytosis, paxillin activation, and cofilin activation positively correlated with one another. Taken together, these observations suggest a novel mechanism whereby paxillin and cofilin are targeted to control phagocytosis by both the activating signaling that phagocytic receptors produce by promoting the activation of paxillin and cofilin and the inhibiting signaling that immune inhibitory SIRPα produces by promoting the inactivation of paxillin and cofilin.
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影响因子：
3.1
作者：
Rotshenker, S
通讯作者：
Rotshenker, S
影响因子：
9.3
作者：
Hadas S;Spira M;Hanisch UK;Reichert F;Rotshenker S
通讯作者：
Rotshenker S
影响因子：
5.3
作者：
Reichert, F;Rotshenker, S
通讯作者：
Rotshenker, S
DOI：
10.1038/nrm2786
发表时间：
2009-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.4
作者：
Mead, RJ;Singhrao, SK;Morgan, BP
通讯作者：
Morgan, BP